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BONE (PART 1)

Dr. Emad I. H. Shaqoura, M.D., M.Sc. Anatomy

Faculty of Medicine, IUG

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OUTLINES

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Functions of bone tissue

Structure of bone

Types of bone

Osteogenesis

Bone growth, remodeling & repair

Joints

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FUNCTIONS OF BONE TISSUE

It provides solid support for the body.
It protects vital organs such as those in the cranial and thoracic cavities.
It houses the bone marrow where blood cells are formed.
It also serves as a reservoir of calcium, phosphate, and other ions.
Bones form a system of levers that multiply the forces generated during skeletal muscle contraction and transform them into bodily movements.

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STRUCTURE OF BONE

Bone is a specialized connective tissue composed of:

Calcified bone matrix , and
Three major cell types, namely osteoblasts, osteocytes & osteoclasts.

All bones are lined on both internal and external surfaces�by endosteum on the internal surface surrounding the marrow�cavity and periosteum on the external surface.

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FIGURE 8-1

Figure 8–1 Components of bone.

A schematic overview of the basic features of bone, including the three key cell types: osteocytes, osteoblasts, and osteoclasts; their usual locations; and the typical lamellar organization of bone. Osteoblasts secrete the matrix that then hardens by calcification, trapping the differentiating cells now called osteocytes in individual lacunae. Osteocytes maintain the calcified matrix and receive nutrients from microvasculature in the central canals of the osteons via very small channels called canaliculi that interconnect the lacunae. Osteoclasts are monocyte-derived cells in bone required for bone remodeling.

The periosteum consists of dense connective tissue, with a primarily fibrous layer covering a more cellular layer. Bone is vascularized by small vessels that penetrate the matrix from the periosteum. Endosteum covers all trabeculae around the marrow cavities.

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METHODS OF PREPARATION

Decalcified sections: can be prepared by decalcifying the bone in an acid solution to remove the calcium salts.

The tissue can then be embedded, sectioned, and routinely stained for study.
Disadvantage: osteocytes are distorted by the decalcifying acid bath.

Ground sections: are prepared by sawing the bone into thin slices, followed by grinding the sections with abrasives between glass plates.

When the section is sufficiently thin for study with light microscope, it is mounted for study.
Disadvantage: the cells are destroyed, and the lacunae and canaliculi are filled in with bone debris.

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BONE CELLS

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Osteoblasts

Synthesize the organic components of the matrix.

Osteocytes

Found in lacunae between bone matrix layers.
Have cytoplasmic processes extending into small canaliculi between lamellae.

Osteoclasts

Multinucleated, giant cells.
Involved in the resorption and�remodeling of bone tissue.

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FIGURE 8-2

Figure 8–2 Bone Tissue.

Newly formed bone tissue decalcified for sectioning and stained with trichrome in which the collagen-rich ECM appears bright blue. The tissue is a combination of mesenchymal regions (M) containing capillaries, fibroblasts, and osteoprogenitor stem cells and regions of normally calcified matrix with varying amounts of collagen and the three major cell types found in all bone tissue. Bone-forming osteoblasts (Ob) differentiate from osteoprogenitor cells in the periosteum and endosteum, and cover the surfaces of existing bone matrix. Osteoblasts secrete osteoid rich in collagen type I, but also containing proteoglycans and other molecules. As osteoid undergoes calcification and hardens, it entraps some osteoblasts which then differentiate further as osteocytes (Oc) occupying lacunae surrounded by bony matrix. The much less numerous large, multinuclear osteoclasts (Ocl), produced by the fusion of blood monocytes, reside on bony surfaces and erode the matrix during bone remodeling. (400X; Mallory trichrome)

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OSTEOBLASTS

Osteoblasts synthesize and secrete the organic components�of bone matrix (osteoid), which include:

Type I collagen fibers.
Proteoglycans.
Several glycoproteins e.g., osteonectin.

Viable osteoblasts are also required for deposition of the inorganic components of bone.

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OSTEOBLASTS (cont’d)

Active osteoblasts are located exclusively at the surfaces of bone matrix bound to it by integrins, forming a layer of cuboidal cells joined together by adherent & gap junctions.
When their synthesizing activity declines, osteoblasts either:

differentiate as osteocytes entrapped in matrix lacunae.
flatten and cover the matrix surface as bone lining cells.
undergo apoptosis (majority of cells).

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FIGURE 8-3

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Wheater's Functional Histology - A Text and Colour Atlas 6^th Ed.

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Wheater's Functional Histology - A Text and Colour Atlas 6^th Ed.

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OSTEOBLASTS (cont’d)

During matrix synthesis, osteoblasts have the ultrastructure of cells actively synthesizing proteins for secretion.

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OSTEOBLASTS (cont’d)

Osteoblasts are polarized cells, producing a layer of new (but not yet calcified) material called osteoid between the osteoblast layer and the preexisting bone surface.
This process of bone appositional growth is completed by subsequent deposition of calcium salts into the newly formed matrix.

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FIGURE 8-3

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OSTEOBLASTS (cont’d)

From their ends adjacent to the matrix, osteoblasts secrete type I collagen, several glycoproteins, and proteoglycans.
Some of these proteins, notably osteocalcin and certain glycoproteins, bind Ca²+ with high affinity, thus raising the local concentration of these ions.
Osteoblasts also release very small membrane-enclosed matrix vesicles rich in alkaline phosphatase and other enzymes.
These enzymes hydrolyze PO4− ions from various macromolecules, creating a high concentration of these ions locally.

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OSTEOBLASTS (cont’d)

The high ion concentrations cause calcified nanocrystals to form in and around the matrix vesicles.
The crystals grow and mineralize further with formation of small growing masses of calcium hydroxyapatite [Ca10(PO4)6(OH)2], which surround the collagen fibers and all other macromolecules.
Eventually the masses of hydroxyapatite merge as a confluent solid bony matrix as calcification of the matrix is completed.

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FIGURE 8-4

Figure 8–4 Mineralization in bone matrix.

From their ends adjacent to the matrix, osteoblasts secrete type I collagen, several glycoproteins, and proteoglycans. Some of these factors, notably osteocalcin and certain glycoproteins, bind Ca²⁺ with high affinity, thus raising the local concentration of these ions. Osteoblasts also release very small membrane-enclosed matrix vesicles with which alkaline phosphatase and other enzymes are associated. These enzymes hydrolyze PO₄⁻ ions from various macromolecules, creating a high concentration of these ions locally.

The high ion concentrations cause calcified nanocrystals to form in and around the matrix vesicles. The crystals grow and mineralize further with formation of small growing masses of calcium hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂], which surround the collagen fibers and all other macromolecules. Eventually the masses of hydroxyapatite merge as a confluent solid bony matrix as calcification of the matrix is completed.

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MEDICAL APPLICATION

Primary bone tumors:

Cancers originating directly from bone cells.
They are fairly uncommon (0.5% of all cancer deaths).
Osteosarcoma can arise in osteoprogenitor cells.

Secondary bone tumors:

The skeleton is often the site of secondary metastatic tumors.
They arise when cancer cells move into bones via small blood or lymphatic vessels from malignancies in other organs, most commonly the breast, lung, prostate gland, kidney, or thyroid gland.

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OSTEOCYTES

As osteoblasts secrete the matrix, some become gradually surrounded by it and differentiate further as osteocytes.
Osteocytes are enclosed singly within the lacunae that are regularly spaced throughout the mineralized matrix.
In the transition from osteoblasts to osteocytes, the cells extend many long dendritic processes, which also become surrounded by calcifying matrix.
Osteocytic processes thus come to occupy the many canaliculi, 250-300 nm in diameter, that radiate from each lacuna.

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Wheater's Functional Histology - A Text and Colour Atlas 6^th Ed.

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FIGURE 8-5

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OSTEOCYTES (cont’d)

Diffusion of metabolites between osteocytes and blood vessels occurs through the small amount of extracellular fluid between the bone matrix and the osteocytes and their processes.
Osteocytes also communicate with one another and with nearby osteoblasts and bone lining cells via gap junctions at the ends of their processes.

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OSTEOCYTES (cont’d)

When compared with osteoblasts, the flat, almond-shaped osteocytes exhibit significantly less RER, smaller Golgi complexes, and more condensed nuclear chromatin.

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OSTEOCYTES (cont’d)

Osteocytes maintain the bony matrix, and their death is followed by rapid matrix resorption.
Osteocytes express different proteins compared to osteoblasts, with paracrine & endocrine effects that help regulate bone remodeling.
The extensive lacunar-canalicular network of these cells and their communication with all other bone cells allow osteocytes to serve as sensitive detectors of stress or fatigue-induced microdamage in bone and to trigger remedial activity in osteoblasts and osteoclasts.

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FIGURE 8-5

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MEDICAL APPLICATION

The network of dendritic processes extending from osteocytes has been called a “mechanostat,” monitoring areas within bones where loading has been increased or decreased, and signaling cells to adjust ion levels and maintain the adjacent bone matrix accordingly.
Lack of exercise (or the weightlessness experienced by astronauts) leads to decreased bone density, due in part to the lack of mechanical stimulation of these cells.

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OSTEOCLASTS

Osteoclasts are very large, motile cells with multiple nuclei.
They play a major role in matrix resorption during bone growth and remodeling.
Osteoclasts originate from the fusion of bone marrow–derived monocytes.
Osteoclast development requires two polypeptides produced by osteoblasts: macrophage-colony–stimulating factor (M-CSF) and the receptor activator of nuclear factor- κB ligand (RANKL).

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FIGURE 8-6

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OSTEOCLASTS (cont’d)

In areas of bone undergoing resorption, osteoclasts lie within enzymatically etched cavities in the matrix known as resorption cavities (or Howship lacunae).
In an active osteoclast the membrane domain that contacts the bone forms a circular sealing zone which binds the cell tightly to the bone matrix and surrounds an area with many surface projections, called the ruffled border.
This circumferential sealing zone allows the formation of a specialized microenvironment between the osteoclast and the matrix in which bone resorption occurs

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FIGURE 8-6

Figure 8–6 Osteoclasts and their activity.

The osteoclast is a large cell with several nuclei derived by the fusion in bone of several blood-derived monocytes.

(b) Diagram showing an osteoclast’s circumferential sealing zone where integrins tightly bind the cell to the bone matrix. The sealing zone surrounds a ruffled border of microvilli and other cytoplasmic projections close to this matrix. The sealed space between the cell and the matrix is acidified to ~pH 4.5 by proton pumps in the ruffled part of the cell membrane and receives secreted matrix metalloproteases and other hydrolytic enzymes. Acidification of the sealed space promotes dissolution of hydroxyapatite from bone and stimulates activity of the protein hydrolases, producing localized matrix resorption. The breakdown products of collagen fibers and other polypeptides are endocytosed by the osteoclast and further degraded in lysosomes, while Ca2+ and other ions are released directly and taken up by the blood.

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FIGURE 8-6

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OSTEOCLASTS (cont’d)

Into this subcellular pocket the osteoclast pumps protons (H+) to acidify and promote dissolution of the adjacent hydroxyapatite, and releases matrix metalloproteinases and other hydrolytic enzymes from lysosome-related secretory vesicles for the localized digestion of matrix proteins.
Osteoclast activity is controlled by local signaling factors from other bone cells.
Osteoblasts activated by parathyroid hormone produce M-CSF, RANKL, and other factors that regulate the formation and activity of osteoclasts.

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MEDICAL APPLICATION

Osteopetrosis, is a genetic disease characterized by dense, heavy bones “marble bones”.
The osteoclasts lack ruffled borders and bone resorption is defective.
This disorder results in overgrowth and thickening of bones, often with obliteration of the marrow cavities, depressing blood cell formation and causing anemia and the loss of white blood cells.
The defective osteoclasts in most patients have mutations in genes for the cells’ proton-ATPase pumps or chloride channels.

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Normal V.S Osteopetrosis X- Ray

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Case courtesy of Dr Wael Nemattalla, Radiopaedia.org, rID: 7417

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MEDICAL APPLICATION

Osteoporosis, frequently found in immobilized patients and in postmenopausal women.
It is an imbalance in skeletal turnover so that bone resorption exceeds bone formation.
This leads to calcium loss from bones and reduced bone mineral density (BMD).
Individuals at risk for osteoporosis are routinely tested for BMD by dual-energy x ray absorptiometry (DEXA scans).

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BONE MATRIX

Inorganic matrix:
Represents about 50% of the dry weight of bone matrix.
Calcium hydroxyapatite is most abundant, but bicarbonate, citrate, magnesium, potassium, and sodium ions are also found.
Significant quantities of non-crystalline calcium phosphate are also present.
The surface ions of hydroxyapatite crystals are hydrated; the layer of water around the crystal facilitates the exchange of ions between the mineral and body fluids.

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BONE MATRIX (cont’d)

Organic matrix:
It is embedded in the calcified matrix & includes type I collagen, small proteoglycans, and multiadhesive glycoproteins such as osteonectin.
Calcium-binding glycoproteins, notably osteocalcin, and the phosphatases released in matrix vesicles by osteoblasts promote calcification of the matrix.
Other tissues containing type I collagen do not contain osteocalcin or matrix vesicles and are not normally calcified.

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BONE MATRIX (cont’d)

Because of its high collagen content, decalcified bone matrix is usually acidophilic.
The association of minerals with collagen fibers during calcification is responsible for the hardness and resistance of bone tissue.
After a bone is decalcified, its shape is preserved, but it becomes as flexible as a tendon.

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PERIOSTEUM & ENDOSTEUM

The periosteum:
Is a double-layered tissue covering the external surface of bone.
The outer layer is a dense connective tissue, with small blood vessels, collagen bundles, and fibroblasts.
Bundles of periosteal collagen fibers, called perforating (or Sharpey) fibers, penetrate the bone matrix, binding the periosteum to bone.
The inner layer of periosteum is a more cellular layer containing bone lining cells, osteoblasts, and mesenchymal stem cells called osteoprogenitor cells.

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FIGURE 8-1

Figure 8–1 Components of bone.

A schematic overview of the basic features of bone, including the three key cell types: osteocytes, osteoblasts, and osteoclasts; their usual locations; and the typical lamellar organization of bone. Osteoblasts secrete the matrix that then hardens by calcification, trapping the differentiating cells now called osteocytes in individual lacunae. Osteocytes maintain the calcified matrix and receive nutrients from microvasculature in the central canals of the osteons via very small channels called canaliculi that interconnect the lacunae. Osteoclasts are monocyte-derived cells in bone required for bone remodeling.

The periosteum consists of dense connective tissue, with a primarily fibrous layer covering a more cellular layer. Bone is vascularized by small vessels that penetrate the matrix from the periosteum. Endosteum covers all trabeculae around the marrow cavities.

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PERIOSTEUM & ENDOSTEUM (cont’d)

Osteoprogenitor cells play a prominent role in bone growth and in bone repair, as they have the potential to proliferate and differentiate into osteoblasts.
The principal functions of periosteum are to nourish the osseous tissue and provide a continuous supply of new osteoblasts for appositional bone growth or repair.
The Endosteum:
It covers small trabeculae of bony matrix that project into the marrow cavities.
The endosteum contains osteoprogenitor cells, osteoblasts, and bone lining cells, but within a sparse matrix of collagen fibers..

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FIGURE 8-3

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TYPES OF BONE

Grossly, cross section shows two bone types:
Compact (cortical) bone: a dense area near the surface & represents 80% of the total bone mass.
Cancellous (trabecular or spongy) bone: deeper areas with numerous interconnecting cavities, constituting about 20% of total bone mass.

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TYPES OF BONE (cont’d)

The distribution of compact & cancellous bones:
In long bones, the epiphyses are composed of spongy bone covered by a thin layer of compact bone.
The diaphysis is almost totally composed of compact bone, with a thin region of spongy bone on the inner surface around the central marrow cavity.
Short bones usually have cores of spongy bone surrounded completely by compact bone.
The flat bones have two layers of compact bone called plates, separated by a thicker layer of spongy bone called the diploë.

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TYPES OF BONE (cont’d)

Microscopic examination of bone tissue shows two types of organization:

Lamellar bone: mature bone.
Woven bone: which is usually more immature than lamellar bone.

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1. LAMELLAR BONE

Most bone in adults, compact or cancellous, is organized as lamellar bone, characterized by multiple layers or lamellae of calcified matrix, each 3-7 μm thick.
The lamellae are organized either parallel to each other or concentrically around a central canal.
In each lamella, type I collagen fibers are aligned in parallel, with the pitch of the fibers’ orientation shifted orthogonally (by about 90 degrees) in successive lamellae.
This highly ordered organization of collagen within lamellar bone is visible under the polarizing light microscope as birefringence; alternating bright and dark layers are due to the changing orientation of collagen fibers in the lamellae.

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FIGURE 8-1

Figure 8–1 Components of bone.

A schematic overview of the basic features of bone, including the three key cell types: osteocytes, osteoblasts, and osteoclasts; their usual locations; and the typical lamellar organization of bone. Osteoblasts secrete the matrix that then hardens by calcification, trapping the differentiating cells now called osteocytes in individual lacunae. Osteocytes maintain the calcified matrix and receive nutrients from microvasculature in the central canals of the osteons via very small channels called canaliculi that interconnect the lacunae. Osteoclasts are monocyte-derived cells in bone required for bone remodeling.

The periosteum consists of dense connective tissue, with a primarily fibrous layer covering a more cellular layer. Bone is vascularized by small vessels that penetrate the matrix from the periosteum. Endosteum covers all trabeculae around the marrow cavities.

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FIGURE 8-8

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FIGURE 8-8

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Bone Lamellae

Osteon

Interstitial Lamellae

Circumferential Lamellae

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OSTEON (HAVERSIAN SYSTEM)

An osteon (or Haversian system) refers to the complex of concentric lamellae surrounding a small central canal that contains blood vessels, nerves, loose connective tissue, and endosteum.
Between successive lamellae are lacunae, each with one osteocyte, interconnected by canaliculi containing the cells’ dendritic processes.
Processes of adjacent cells are in contact via gap junctions, and all cells of an osteon receive nutrients and oxygen from the microvasculature in the central canal .
The outer boundary of each osteon is called the cement line which includes many more non-collagen proteins in addition to mineral and collagen.

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FIGURE 8-1

Figure 8–1 Components of bone.

A schematic overview of the basic features of bone, including the three key cell types: osteocytes, osteoblasts, and osteoclasts; their usual locations; and the typical lamellar organization of bone. Osteoblasts secrete the matrix that then hardens by calcification, trapping the differentiating cells now called osteocytes in individual lacunae. Osteocytes maintain the calcified matrix and receive nutrients from microvasculature in the central canals of the osteons via very small channels called canaliculi that interconnect the lacunae. Osteoclasts are monocyte-derived cells in bone required for bone remodeling.

The periosteum consists of dense connective tissue, with a primarily fibrous layer covering a more cellular layer. Bone is vascularized by small vessels that penetrate the matrix from the periosteum. Endosteum covers all trabeculae around the marrow cavities.

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FIGURE 8-9

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OSTEON (HAVERSIAN SYSTEM) cont’d

Each osteon is a long, sometimes bifurcated, cylinder generally parallel to the long axis of the diaphysis.
It consists of a central canal surrounded by 5-20 concentric lamellae.
The central canals communicate with the marrow cavity and the periosteum and with one another through transverse perforating canals (or Volkmann canals).
The transverse canals have few, if any, concentric lamellae.
All central canals and perforating canals form when matrix is laid down around areas with preexisting blood vessels.

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INTERSTITIAL LAMELLAE

Interstitial lamellae are numerous irregularly shaped groups of parallel lamellae, scattered among the intact osteons.

These structures are lamellae remaining from osteons partially destroyed by osteoclasts during growth and remodeling of bone.

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FIGURE 8-10

Figure 8–10 Lamellar bone: Perforating canals and interstitial lamellae.

(a) Transverse perforating (Volkmann) canals (P) connecting adjacent osteons are shown in this micrograph of compact lamellar bone. Such canals “perforate” lamellae and provide another source of microvasculature for the central canals of osteons. Among the intact osteons are also found remnants of eroded osteons, seen as irregular interstitial lamellae (I). Ground bone. X100.

(b) Schematic diagram shows remodeling of compact lamellar bone with three generations of osteons and their successive contributions to the formation of interstitial lamellae. The shading indicates that successive generations of osteons have different degrees of mineralization, with the most newly formed being the least mineralized. Remodeling is a continuous process that involves the coordinated activity of osteoblasts and osteoclasts, and is responsible for adaptation of bone to changes in stress, especially during the body’s growth.

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CIRCUMFERENTIAL LAMELLAE

Compact bone (e.g., the diaphysis of long bones), also includes parallel lamellae organized as:
Inner circumferential lamellae: located around the marrow cavity.
External circumferential lamellae: located immediately beneath the periosteum.

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FIGURE 8-1

Figure 8–1 Components of bone.

A schematic overview of the basic features of bone, including the three key cell types: osteocytes, osteoblasts, and osteoclasts; their usual locations; and the typical lamellar organization of bone. Osteoblasts secrete the matrix that then hardens by calcification, trapping the differentiating cells now called osteocytes in individual lacunae. Osteocytes maintain the calcified matrix and receive nutrients from microvasculature in the central canals of the osteons via very small channels called canaliculi that interconnect the lacunae. Osteoclasts are monocyte-derived cells in bone required for bone remodeling.

The periosteum consists of dense connective tissue, with a primarily fibrous layer covering a more cellular layer. Bone is vascularized by small vessels that penetrate the matrix from the periosteum. Endosteum covers all trabeculae around the marrow cavities.

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BONE REMODELING

Bone remodeling is continuous throughout life and involves a process of bone resorption and bone formation.
In compact bone, remodeling resorbs parts of old osteons and produces new ones.
Osteoclasts often work in groups to remove old bone in tunnel-like cavities having the approximate diameter of new osteons.

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BONE REMODELING (cont’d)

Such tunnels are quickly invaded by many osteoprogenitor cells from the endosteum or periosteum and sprouting loops of capillaries.
Osteoblasts develop, line the wall of the tunnels, and begin to secrete osteoid in a cyclic manner, forming the concentric lamellae of bone with trapped osteocytes.
In healthy adults 5%-10% of the bone turns over annually.

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FIGURE 8-11

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FIGURE 8-11

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2. WOVEN BONE

Woven bone is non-lamellar and characterized by random disposition of type I collagen fibers and is the first bone tissue to appear in embryonic development and in fracture repair.
Woven bone tissue is usually temporary and is replaced in adults by lamellar bone, except in a very few places in the body, for example, near the sutures of the calvaria and in the insertions of some tendons.
This type of bone has a lower mineral content (it is more easily penetrated by x-rays) and often a higher proportion of osteocytes than mature lamellar bone.
These features reflect the fact that woven bone forms more quickly but has less strength than lamellar bone.

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Wheater's Functional Histology - A Text and Colour Atlas 6^th Ed.

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TYPES OF BONE (cont’d)

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REFERENCES

Junqueira's Basic Histology, Text & Atlas, 15^th Ed.
Wheater's Functional Histology - A Text and Colour Atlas 6^th Ed.
@ Elsevier. Gartner & Hiatt. Color Textbook of Histology 3^rd Ed.

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Thank You ☺

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BONE (PART 2)

Dr. Emad I. H. Shaqoura, M.D., M.Sc. Anatomy

Faculty of Medicine, IUG

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OUTLINES

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Functions of bone tissue

Structure of bone

Types of bone

Osteogenesis

Bone growth, remodeling & repair

Joints

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OSTEOGENESIS

Bone development or osteogenesis occurs by one of two processes:
Intramembranous ossification, in which osteoblasts differentiate directly from mesenchyme and begin secreting osteoid.
Endochondral ossification, in which a preexisting matrix of hyaline cartilage is eroded and invaded by osteoblasts, which then begin osteoid production.
The bone forms initially; in both processes, is temporary woven bone, which is soon replaced by stronger lamellar bone.
During growth of all bones, areas of woven bone, areas of bone resorption, and areas of lamellar bone all exist contiguous to one another.

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MEDICAL APPLICATION

Osteogenesis imperfecta, or “brittle bone disease,” refers to a group of related congenital disorders in which the osteoblasts produce deficient amounts of type I collagen or defective type I collagen due to genetic mutations.

Such defects lead to significant fragility of the bones. (*)

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1. INTRAMEMBRANOUS OSSIFICATION

Intramembranous ossification, is so called because it takes place within condensations “membranes” of embryonic mesenchymal tissue.
Most bones of the skull and jaws, as well as the scapula and clavicle, are formed embryonically by intramembranous ossification.

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1. INTRAMEMBRANOUS OSSIFICATION

The starting points for bone formation within the mesenchyme are called ossification centers.
In these areas mesenchymal cells differentiate into osteoprogenitor cells which proliferate and form incomplete layers of osteoblasts around a network of developing capillaries.
Osteoblasts secrete the osteoid away from these blood vessels, that later calcify and form trabeculae of woven bone.

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FIGURE 8-13

Figure 8–13 Intramembranous ossification.

A section of fetal pig mandible developing by intramembranous ossification. (a) Areas of typical mesenchyme (M) and condensed mesenchyme (CM) are adjacent to layers of new osteoblasts (O). Some osteoblasts have secreted matrices of bone (B), the surfaces of which remain covered by osteoblasts. Between these trabeculae of new woven bone are areas with small blood vessels (V). X40. H&E.

(b) At higher magnification another section shows these same structures, along with the developing periosteum (P) adjacent to masses of woven bone that will soon merge to form a continuous plate of bone. The larger mesenchyme-filled region at the top is part of the developing marrow cavity. Osteocytes in lacunae can be seen within the eosinophilic bony matrix. X100. H&E.

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1. INTRAMEMBRANOUS OSSIFICATION

Differentiating osteocytes within lacunae retain intercellular contacts via their cytoplasmic processes within canaliculi.
Continued matrix secretion, calcification, and trabecular growth lead slowly to the fusion of neighboring ossification centers and gradually produce layers of compact bone that broadly enclose a region of cancellous bone with marrow and larger blood vessels.

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FIGURE 8-13

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1. INTRAMEMBRANOUS OSSIFICATION

In cranial flat bones, bone formation predominates over bone resorption at both the internal and external surfaces.
Thus, two layers of compact bone (internal and external plates) arise, while the central portion (diploë) maintains its cancellous, spongy nature.
The fontanelles or “soft spots” on the heads of newborn infants are areas in the skull that correspond to parts of the connective tissue that are not yet ossified.
Regions of the connective tissue that do not undergo ossification give rise to the endosteum and the periosteum of the new bone.

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2. ENDOCHONDRAL OSSIFICATION

Endochondral ossification takes place within a piece of hyaline cartilage whose shape resembles a model, of the bone to be formed.
This type of ossification is responsible for forming most bones of the body and is especially well studied in developing long bones.

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FIGURE 8-14

Figure 8–14 Osteogenesis of long bones by endochondral ossification.

This process, by which most bones form initially, begins with embryonic models of the skeletal elements made of hyaline cartilage (1). Late in the first trimester, a bone collar develops beneath the perichondrium around the middle of the long bones’ cartilage models, causing degeneration of the underlying cartilage (2).

This is followed by invasion of the degenerating cartilage by capillaries and osteoprogenitor cells from what is now the periosteum to produce a primary ossification center in the diaphysis (3). Here osteoid is deposited by the new osteoblasts, undergoes calcification into woven bone, and is remodeled as compact bone.

(4) Around the time of birth secondary ossification centers begin to develop by a similar process in the epiphyses. During childhood the primary and secondary ossification centers gradually come to be separated only by the epiphyseal plate (5) that provides for continued bone elongation. The two ossification centers do not merge until the epiphyseal plate disappears (6) when full stature is achieved. Osteoblasts of the periosteum provide for growth in the bone’s diameter.

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2. ENDOCHONDRAL OSSIFICATION

The first bone tissue appears as a collar surrounding the diaphysis of the cartilage model.
This bone collar is produced by osteoblasts that form within the surrounding perichondrium.
The collar impedes diffusion of oxygen and nutrients into the underlying cartilage, promoting its degeneration.

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2. ENDOCHONDRAL OSSIFICATION

The chondrocytes begin to produce osteocalcin & alkaline phosphatase and hypertrophy, enlarging their lacunae.
These changes both compress the matrix into narrow trabeculae and lead to calcification in these structures.
Death of the chondrocytes creates a porous structure consisting of calcified cartilage remnants which become covered by a layer of osteoblasts.

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FIGURE 8-15

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2. ENDOCHONDRAL OSSIFICATION

Blood vessels from the perichondrium (now the periosteum) penetrate through the bone collar, bringing osteoprogenitor cells to the porous central region.
Next, osteoblasts adhere to the remnants of calcified cartilage matrix and produce woven bone.
The calcified cartilage at this stage appears basophilic, and the new bone is more acidophilic.
This process in the diaphysis forms the primary ossification center, beginning in many bones as early as the first trimester.

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2. ENDOCHONDRAL OSSIFICATION

Secondary ossification centers appear later at the epiphyses of the cartilage model.
During their expansion and remodeling, the primary and secondary ossification centers produce cavities that are gradually filed with bone marrow and trabeculae of cancellous bone.
With the primary and secondary ossification centers, two regions of cartilage remain:

Articular cartilage covering the articular surfaces in joints.
Epiphyseal cartilage: between the epiphysis and the diaphysis, responsible for elongation of bone till the age of 20, where it is closed and transformed into epiphyseal line.

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FIGURE 8-16

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EPIPHYSEAL PLATE

An epiphyseal growth plate shows five distinct zones of cellular activity, starting from the thin region of normal cartilage:
The resting zone consists of typical hyaline cartilage.
In the proliferative zone, chondrocytes begin to divide rapidly and form columns of stacked cells parallel to the long axis of the bone.

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EPIPHYSEAL PLATE

The hypertrophic cartilage zone contains swollen, terminally differentiated chondrocytes which compress the matrix into aligned spicules and stiffen it by secretion of type X collagen. Unique to the hypertrophic chondrocytes in developing (or fractured) bone, type X collagen limits diffusion in the matrix and with growth factors promotes vascularization from the adjacent primary ossification center.

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FIGURE 8-16

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2. ENDOCHONDRAL OSSIFICATION

In the calcified cartilage zone, loss of the chondrocytes by apoptosis is accompanied by calcification of the septa of cartilage matrix by the formation of hydroxyapatite crystals.
In the ossification zone, bone tissue first appears.

Capillaries and osteoprogenitor cells originally from the periosteum invade the cavities left by the chondrocytes.

Many of these cavities will be merged and become the marrow cavity.

Osteoblasts settle in a layer over the septa of calcified cartilage matrix and secrete osteoid over these structures, forming woven bone.

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FIGURE 8-16

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FIGURE 8-17

Figure 8–17 Cells and matrices of the epiphyseal growth plate.

(a) At the top of the micrograph the growth plate (GP) shows its zones of hyaline cartilage with chondrocytes at rest (R), proliferating (P), and hypertrophying (H). As the chondrocytes swell and degenerate, they release phosphatase, activities that compress the matrix and cause an initial deposition of calcium phosphate. This produces calcified spicules (C) in the former cartilage matrix. The tunnel-like lacunae in which the chondrocytes have undergone apoptosis are invaded from the diaphysis by capillaries that begin to convert these spaces into marrow (M) cavities. Endosteum with osteoblasts also moves in from the diaphyseal primary ossification center, covering the spicules of calcified cartilage and laying down layers of osteoid to form a matrix of woven bone (B). X40. H&E.

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FIGURE 8-17

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MEDICAL APPLICATION

Calcium deficiency in children can lead to rickets, a disease in which the bone matrix does not calcify normally and the epiphyseal plate can become distorted by the normal strains of body weight and muscular activity.
Ossification processes are consequently impeded, which causes bones to grow more slowly and often become deformed.
The deficiency can be due either to insufficient calcium in the diet or a failure to produce the steroid prohormone vitamin D, which is important for the absorption of Ca2 + by cells of the small intestine.

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MEDICAL APPLICATION (cont’d)

In adults, calcium deficiency can give rise to osteomalacia (osteon + gr. malakia, softness), characterized by deficient calcification of recently formed bone and partial decalcification of already calcified matrix.

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BONE GROWTH, REMODELING, & REPAIR

Osteogenesis and bone growth involves the partial resorption of old bone tissue, while simultaneously forming new bone at a rate exceeding that of bone removal.
The rate of bone turnover is very active in young children, where it can be 200 times faster than that of adults.
The constant remodeling of bone ensures that, despite its hardness, this tissue remains plastic and capable of adapting its internal structural in the face of changing stresses.
A well known example of bone plasticity is the ability to modify the positions of teeth by the lateral pressures produced by orthodontic appliances.

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BONE GROWTH, REMODELING, & REPAIR

Bone forms on the side where traction is applied and is resorbed on the opposite side where pressure is exerted.
In this way, teeth are moved within the jaw while the bone is being remodeled.

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BONE GROWTH, REMODELING, & REPAIR

Because it contains osteoprogenitor stem cells in the periosteum, endosteum, and marrow and is very well vascularized, bone normally has an excellent capacity for repair.

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MEDICAL APPLICATION

Bone fractures are repaired through fibrocartilage formation and osteogenic activity of the major bone cells.
Bone fractures disrupt blood vessels, causing bone cells near the break to die.
The damaged blood vessels produce a localized hemorrhage or hematoma.
Clotted blood & tissue debris is removed by macrophages and damaged bone is resorbed by osteoclasts.
The periosteum and the endosteum produce a soft callus of fibrocartilage-like tissue that surrounds the fracture and covers the extremities of the fractured bone.

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MEDICAL APPLICATION (cont’d)

The fibrocartilaginous callus is gradually replaced in a process of combined endochondral and intramembranous ossification.
This produces a hard callus of woven bone around the fractured ends of bone.
Stresses imposed on the bone during repair and during the patient’s gradual return to activity serve to remodel the bone callus.
The immature, woven bone of the callus is gradually resorbed and replaced by lamellar bone, thus restoring the original bone structure.

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FIGURE 8-18

Figure 8–18 Main features of bone fracture repair.

Repair of a fractured bone occurs through several stages but utilizes mechanisms already in place for bone remodeling. (a) Blood vessels torn within the fracture release blood that clots to produce a large fracture hematoma. (b) This is gradually removed by macrophages and replaced by a soft fibrocartilage-like mass of procallus tissue rich in collagen and fibroblasts. If broken, the periosteum reestablishes continuity over this tissue. (c) This soft procallus is invaded by regrowing blood vessels and osteoblasts. In the next few weeks the fibrocartilage is gradually replaced by trabeculae of woven bone, forming a hard callus throughout the original area of fracture. (d) The woven bone is then remodeled as compact and cancellous bone in continuity with the adjacent uninjured areas and fully functional vasculature is reestablished.

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MEDICAL APPLICATION

PTH, calcitonin, and several other hormones act on bone.
The anterior pituitary synthesizes growth hormone, which stimulates the liver to produce insulin-like growth factor-1 (IGF-1).
IGF has a growth-promoting effect, especially on the epiphyseal cartilage.
Consequently, lack of growth hormone during the growing years causes pituitary dwarfism; an excess of growth hormone causes excessive growth of the long bones, resulting in gigantism.
Adult bones cannot increase in length even with excess IGF because they lack epiphyseal cartilage, but they do increase in width by periosteal growth.
In adults, an increase in GH causes acromegaly, a disease in which the bones—mainly the long ones—become very thick.

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JOINTS

Joints are regions where adjacent bones are capped and held together firmly by connective tissues.
The type of joint determines the degree of movement between the bones.
Those that are closely bound together with only a minimum of/ or no movement between them are called synarthroses.
Joints in which the bones are free to articulate over a fairly wide range of motion are classified as diarthroses.

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JOINTS (cont’d)

There are three types of synarthrosis joints according to the tissue making up the union:
Synostosis: There is no movement, and joint-uniting tissue is bone (e.g., skull bones in adults).
Syndesmoses: join bones by dense connective tissue only. Examples include the interosseous ligament of the inferior tibiofibular joint and the posterior region of the sacroiliac joints.
Symphyses: There is little movement, and bones are joined by fibrocartilage (e.g., pubic symphysis & IVD).

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JOINTS (cont’d)

Intervertebral discs:
They are thick discs of fibrocartilage between successive vertebral bodies.
These joints facilitate movements of the vertebral column.
The disc is composed of two parts:

The annulus fibrosus: is mainly composed of overlapping laminae of fibrocartilage in which collagen bundles are orthogonally arranged in adjacent layers.
The multiple lamellae provide the disc with unusual resilience and enable it to withstand pressures generated by the vertebrae.

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JOINTS (cont’d)

The nucleus pulposus: is situated in the center of the annulus fibrosus and allows each disc to function as a shock absorber within the vertebral column.
It typically contains scattered, vacuolated cells (the only cells derived from the embryonic notochord), but it is largely composed of water in a gel-like matrix rich in hyaluronan and fibers of type II collagen.
The nucleus pulposus is large in children, but these structures gradually become smaller with age and are partially replaced by fibrocartilage.

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FIGURE 8-22

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MEDICAL APPLICATION

Within an intervertebral disc, collagen loss or other degenerative changes in the annulus fibrosus are often accompanied by displacement of the nucleus pulposus, a condition variously called a slipped or herniated disc.
This occurs most frequently on the posterior region of the intervertebral disc where there are fewer collagen bundles.
The affected disc frequently dislocates or shifts slightly from its normal position.
If it moves toward nerve plexuses, it can compress the nerves and result in severe pain and other neurologic disturbances.
The pain accompanying a slipped disc may be perceived in areas innervated by the compressed nerve fibers—usually the lower lumbar region.

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JOINTS (cont’d)

Diarthroses such as the elbow and knee generally unite long bones and allow great mobility.
In a diarthrosis, ligaments and a capsule of dense connective tissue maintain proper alignment of the bones.
The capsule encloses a sealed joint cavity that contains synovial fluid, a clear, viscous liquid.
The joint cavity is lined by a specialized connective tissue called the synovial membrane that extends folds and villi into the cavity and secretes the lubricant synovial fluid.

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FIGURE 8-19

Figure 8–19 Diarthroses or synovial joints.

Diarthroses are joints that allow free movement of the attached bones, such as knuckles, knees, and elbows.

(a) Diagram showing major components of a diarthrosis, including the articular capsule continuous with a ligament inserting into the periosteum of both bones; the joint cavity containing synovial fluid as a lubricant; and the ends of epiphyses covered by articular cartilage. The synovial membrane lines the capsule and produces the synovial fluid.

(b) Longitudinal section through a diarthrosis with growing bones of a rodent knee, showing the position near the boundaries of the capsule (C) of the epiphyseal growth plate (E) where endochondral ossification occurs. Also shown are the articular cartilage (A) and the folds of synovial membrane (SM), which extend prominently into the joint cavity from connective tissue of the capsule for production of synovial fluid. X10. PSH stain.

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FIGURE 8-19

Figure 8–19 Diarthroses or synovial joints.

Diarthroses are joints that allow free movement of the attached bones, such as knuckles, knees, and elbows.

(a) Diagram showing major components of a diarthrosis, including the articular capsule continuous with a ligament inserting into the periosteum of both bones; the joint cavity containing synovial fluid as a lubricant; and the ends of epiphyses covered by articular cartilage. The synovial membrane lines the capsule and produces the synovial fluid.

(b) Longitudinal section through a diarthrosis with growing bones of a rodent knee, showing the position near the boundaries of the capsule (C) of the epiphyseal growth plate (E) where endochondral ossification occurs. Also shown are the articular cartilage (A) and the folds of synovial membrane (SM), which extend prominently into the joint cavity from connective tissue of the capsule for production of synovial fluid. X10. PSH stain.

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JOINTS (cont’d)

Synovial fluid is derived from blood plasma, but with a high concentration of hyaluronan produced by cells of the synovial membrane.
In different diarthrotic joints the synovial membrane may�have prominent regions with dense connective tissue or fat.
However the tissue’s surface region is usually well vascularized, with many porous (fenestrated) capillaries.

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JOINTS (cont’d)

The synovial membrane contains cells of connective tissue proper and a changing population of leukocytes, is characterized by two specialized cells with distinctly different functions and origins:
Macrophage-like synovial cells, also called type A cells.
Fibroblastic synovial cells, or type B cells.

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JOINTS (cont’d)

Type A cells:
Are modified macrophages derived from blood monocytes and remove wear-and-tear debris from the synovial fluid.
These cells represent approximately 25% of the cells lining the synovium, are important in regulating inflammatory events within diarthrotic joints.
Type B cells:
Produce abundant hyaluronan and other extracellular components.
Much of this material is transported by water from the capillaries into the synovial fluid, which lubricates the joint, reducing friction on all internal surfaces, and supplies nutrients and oxygen to the articular cartilage.

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FIGURE 8-20

Figure 8–20 Synovial membrane.

The synovial membrane is a specialized connective tissue that lines capsules of synovial joints and contacts the synovial fluid lubricant, which it is primarily responsible for maintaining. (a) The synovial membrane projects folds into the joint cavity (JC) and these contain many small blood vessels (V). The joint cavity surrounds the articular cartilage (AC). X100. Mallory trichrome.

(b) Higher magnification of the fold showing a high density of capillaries and two specialized types of cells called synoviocytes. Contacting the synovial fluid at the tissue surface are many rounded macrophage-like synovial cells (type A) derived from blood monocytes. These cells bind, engulf, and remove tissue debris from synovial fluid. These cells often form a layer at the tissue surface (A) and can superficially resemble an epithelium, but there is no basal lamina and the cells are not joined together by cell junctions. Fibroblast-like (type B) synovial cells (B) are mesenchymally derived and specialized for synthesis of hyaluronan that enters the synovial fluid, replenishing it. X400.

(c) Schematic representation of synovial membrane histology. Among the macrophage-like and fibroblast-like synovial cells are collagen fibers and other typical components of connective tissue. Surface cells have no basement membrane or junctional complexes denoting an epithelium, despite the superficial resemblance. Blood capillaries are fenestrated, which facilitates exchange of substances between blood and synovial fluid.

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FIGURE 8-20

Figure 8–20 Synovial membrane.

The synovial membrane is a specialized connective tissue that lines capsules of synovial joints and contacts the synovial fluid lubricant, which it is primarily responsible for maintaining. (a) The synovial membrane projects folds into the joint cavity (JC) and these contain many small blood vessels (V). The joint cavity surrounds the articular cartilage (AC). X100. Mallory trichrome.

(b) Higher magnification of the fold showing a high density of capillaries and two specialized types of cells called synoviocytes. Contacting the synovial fluid at the tissue surface are many rounded macrophage-like synovial cells (type A) derived from blood monocytes. These cells bind, engulf, and remove tissue debris from synovial fluid. These cells often form a layer at the tissue surface (A) and can superficially resemble an epithelium, but there is no basal lamina and the cells are not joined together by cell junctions. Fibroblast-like (type B) synovial cells (B) are mesenchymally derived and specialized for synthesis of hyaluronan that enters the synovial fluid, replenishing it. X400.

(c) Schematic representation of synovial membrane histology. Among the macrophage-like and fibroblast-like synovial cells are collagen fibers and other typical components of connective tissue. Surface cells have no basement membrane or junctional complexes denoting an epithelium, despite the superficial resemblance. Blood capillaries are fenestrated, which facilitates exchange of substances between blood and synovial fluid.

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FIGURE 8-20

Figure 8–20 Synovial membrane.

The synovial membrane is a specialized connective tissue that lines capsules of synovial joints and contacts the synovial fluid lubricant, which it is primarily responsible for maintaining. (a) The synovial membrane projects folds into the joint cavity (JC) and these contain many small blood vessels (V). The joint cavity surrounds the articular cartilage (AC). X100. Mallory trichrome.

(b) Higher magnification of the fold showing a high density of capillaries and two specialized types of cells called synoviocytes. Contacting the synovial fluid at the tissue surface are many rounded macrophage-like synovial cells (type A) derived from blood monocytes. These cells bind, engulf, and remove tissue debris from synovial fluid. These cells often form a layer at the tissue surface (A) and can superficially resemble an epithelium, but there is no basal lamina and the cells are not joined together by cell junctions. Fibroblast-like (type B) synovial cells (B) are mesenchymally derived and specialized for synthesis of hyaluronan that enters the synovial fluid, replenishing it. X400.

(c) Schematic representation of synovial membrane histology. Among the macrophage-like and fibroblast-like synovial cells are collagen fibers and other typical components of connective tissue. Surface cells have no basement membrane or junctional complexes denoting an epithelium, despite the superficial resemblance. Blood capillaries are fenestrated, which facilitates exchange of substances between blood and synovial fluid.

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JOINTS (cont’d)

In the hyaline articular cartilage, collagen fibers of are disposed as arches with their tops near the exposed surface, which is not covered by perichondrium.
This arrangement of collagen helps distribute the forces generated by pressure on joints.
The resilient articular cartilage is also an efficient absorber of the intermittent mechanical pressures.

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FIGURE 8-21

Figure 8–21 Articular cartilage.

(a) Articular surfaces of a diarthrosis are made of hyaline cartilage that lacks the usual perichondrium covering. X40. H&E. (b) The large diagram shows a small region of articular cartilage in which collagen fibers run perpendicular to the tissue surface and then bend gradually, forming a broad arch parallel to that surface. The lower left diagram shows a 3D view of collagen fibers in articular cartilage. Proteoglycan aggregates bound to hyaluronic acid and collagen fill the space among the collagen fibers and bind a large amount of water, functioning as a biomechanical spring in articular cartilage. When pressure is applied, some water is forced out of the cartilage matrix into the synovial fluid. When pressure is released, water is attracted back into the interstices of the matrix. These water movements are brought about constantly by using the joint and are essential for nutrition of the cartilage and for facilitating the interchange of O₂, CO₂, and other molecules between the synovial fluid and the articular cartilage.

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FIGURE 8-21

Figure 8–21 Articular cartilage.

(a) Articular surfaces of a diarthrosis are made of hyaline cartilage that lacks the usual perichondrium covering. X40. H&E. (b) The large diagram shows a small region of articular cartilage in which collagen fibers run perpendicular to the tissue surface and then bend gradually, forming a broad arch parallel to that surface. The lower left diagram shows a 3D view of collagen fibers in articular cartilage. Proteoglycan aggregates bound to hyaluronic acid and collagen fill the space among the collagen fibers and bind a large amount of water, functioning as a biomechanical spring in articular cartilage. When pressure is applied, some water is forced out of the cartilage matrix into the synovial fluid. When pressure is released, water is attracted back into the interstices of the matrix. These water movements are brought about constantly by using the joint and are essential for nutrition of the cartilage and for facilitating the interchange of O₂, CO₂, and other molecules between the synovial fluid and the articular cartilage.

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MEDICAL APPLICATION

In rheumatoid arthritis, chronic inflammation of the synovial membrane causes its thickening and stimulates the macrophages to release collagenases and other hydrolytic enzymes.
Such enzymes eventually cause destruction of the articular cartilage, allowing direct contact of the bones projecting into the joint.

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REFERENCES

Junqueira's Basic Histology, Text & Atlas, 15^th Ed.
Wheater's Functional Histology - A Text and Colour Atlas 6^th Ed.
@ Elsevier. Gartner & Hiatt. Color Textbook of Histology 3^rd Ed.

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Thank You ☺