Bone Is A Mineralized Connective Tissue

Bone contains both organic and inorganic material. The organic matter is mainly protein. The principal proteins of bone are listed in Table 48-9; type I collagen is the major protein, comprising 90-95% of the organic material. Type V collagen is also present in small amounts, as are a number of noncollagen proteins, some of which are relatively specific to bone. The inorganic or mineral component is mainly crystalline hydroxyapatite—Ca10(PO4)6(OH)2—along with sodium, magnesium, carbonate, and fluoride; approximately 99% of the body's calcium is contained in bone (Chapter 45). Hydroxyapatite confers on bone the strength and resilience required by its physiologic roles.

Bone is a dynamic structure that undergoes continuing cycles of remodeling, consisting of resorption followed by deposition of new bone tissue. This remodeling permits bone to adapt to both physical (eg, increases in weight-bearing) and hormonal signals.

The major cell types involved in bone resorption and deposition are osteoclasts and osteoblasts (Figure 48-11). The former are associated with resorption and the latter with deposition of bone. Osteocytes are descended from osteoblasts; they also appear to be involved in maintenance of bone matrix but will not be discussed further here.

Osteoclasts are multinucleated cells derived from pluripotent hematopoietic stem cells. Osteoclasts possess an apical membrane domain, exhibiting a ruffled border that plays a key role in bone resorption (Figure 48-12). A proton-translocating ATPase expels protons across the ruffled border into the resorption area, which is the microenvironment of low pH shown in the figure. This lowers the local pH to 4.0 or less, thus increasing the solubility of hydroxyapatite and allowing demineralization to occur. Lysosomal acid proteases are released that digest the now accessible matrix proteins.

Figure 48-12. Schematic illustration of some aspects of the role of the osteoclast in bone resorption. Lysosomal enzymes and hydrogen ions are released into the confined microenvironment created by the attachment between bone matrix and the peripheral clear zone of the osteoclast. The acidification of this confined space facilitates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases. Bone matrix is thus removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, probably digested further, and transferred into capillaries. The chemical equation shown in the figure refers to the action of carbonic anhydrase II, described in the text. (Reproduced, with permission, from Jun-queira LC, Carneiro J: Basic Histology. Text & Atlas, 10th ed. McGraw-Hill, 2003.)

Figure 48-12. Schematic illustration of some aspects of the role of the osteoclast in bone resorption. Lysosomal enzymes and hydrogen ions are released into the confined microenvironment created by the attachment between bone matrix and the peripheral clear zone of the osteoclast. The acidification of this confined space facilitates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases. Bone matrix is thus removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, probably digested further, and transferred into capillaries. The chemical equation shown in the figure refers to the action of carbonic anhydrase II, described in the text. (Reproduced, with permission, from Jun-queira LC, Carneiro J: Basic Histology. Text & Atlas, 10th ed. McGraw-Hill, 2003.)

Osteoblasts—mononuclear cells derived from pluripotent mesenchymal precursors—synthesize most of the proteins found in bone (Table 48-9) as well as various growth factors and cytokines. They are responsible for the deposition of new bone matrix (osteoid) and its subsequent mineralization. Osteoblasts control mineralization by regulating the passage of calcium and phosphate ions across their surface membranes. The latter contain alkaline phosphatase, which is used to generate phosphate ions from organic phosphates. The mechanisms involved in mineralization are not fully understood, but several factors have been implicated. Alkaline phosphatase contributes to mineralization but in itself is not sufficient. Small vesicles (matrix vesicles) containing calcium and phosphate have been described at sites of mineralization, but their role is not clear. Type I collagen appears to be necessary, with mineralization being first evident in the gaps between successive molecules.

Recent interest has focused on acidic phosphoproteins, such as bone sialoprotein, acting as sites of nucleation. These proteins contain motifs (eg, poly-Asp and poly-Glu stretches) that bind calcium and may provide an initial scaffold for mineralization. Some macromole-cules, such as certain proteoglycans and glycoproteins, can also act as inhibitors of nucleation.

It is estimated that approximately 4% of compact bone is renewed annually in the typical healthy adult, whereas approximately 20% of trabecular bone is replaced.

Many factors are involved in the regulation of bone metabolism, only a few of which will be mentioned here. Some stimulate osteoblasts (eg, parathyroid hormone and 1,25-dihydroxycholecalciferol) and others inhibit them (eg, corticosteroids). Parathyroid hormone and 1,25-dihydroxycholecalciferol also stimulate osteoclasts, whereas calcitonin and estrogens inhibit them.

Table48-10. Some metabolic and genetic diseases affecting bone and cartilage.

Disease

Comments

Dwarfism

Often due to a deficiency of growth hormone, but has many other causes.

Rickets

Due to a deficiency of vitamin D during childhood.

Osteomalacia

Due to a deficiency of vitamin D during adulthood.

Hyperparathyroidism

Excess parathormone causes bone resorption.

Osteogenesis imperfecta (eg, MIM 166200)

Due to a variety of mutations in the COL1A1 and COL1A2 genes affecting the synthesis and structure of type I collagen.

Osteoporosis

Commonly postmenopausal or in other cases is more gradual and related to age; a small number of cases are due to mutations in the COL1A1 and COL1A2 genes and possibly in the vitamin D receptor gene (MIM 166710)

Osteoarthritis

A small number of cases are due to mutations in the COL1A genes.

Several chondro-dysplasias

Due to mutations in COL2A1 genes.

Pfeiffer syndrome1 (MIM 100600)

Mutations in the gene encoding fibroblast growth receptor 1 (FGFR1).

Jackson-Weiss (MIM 123150) and Crouzon (MIM 123500) syndromes1

Mutations in the gene encoding FGFR2.

Achondroplasia (MIM 100800) and thanatophoric dysplasia2 (MIM 187600)

Mutations in the gene encoding FGFR3.

1The Pfeiffer, Jackson-Weiss, and Crouzon syndromes are cran-iosynostosis syndromes; craniosynostosis is a term signifying premature fusion of sutures in the skull.

thanatophoric (Gk thanatos "death" + phoros "bearing") dysplasia is the most common neonatal lethal skeletal dysplasia, displaying features similar to those of homozygous achondroplasia.

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