Bone is a dynamic tissue that is remodeled constantly throughout life. The arrangement of compact and cancellous bone provides strength and density suitable for both mobility and protection. In addition, bone provides a reservoir for calcium, magnesium, phosphorus, sodium, and other ions necessary for homeostatic functions. Bone also hosts and regulates hematopoiesis by providing niches for hematopoietic cell proliferation and differentiation. The skeleton is highly vascular and receives about 10% of the cardiac output. Remodeling of bone is accomplished by two distinct cell types: osteoblasts produce bone matrix, and osteoclasts resorb the matrix.
The extracellular components of bone consist of a solid mineral phase in close association with an organic matrix, of which 90–95% is type I collagen (Chap. 363). The noncollagenous portion of the organic matrix is heterogeneous and contains serum proteins such as albumin as well as many locally produced proteins, whose functions are incompletely understood. Those proteins include cell attachment/signaling proteins such as thrombospondin, osteopontin, and fibronectin; calcium-binding proteins such as matrix gla protein and osteocalcin; and proteoglycans such as biglycan and decorin. Some of the proteins organize collagen fibrils; others influence mineralization and binding of the mineral phase to the matrix.
The mineral phase is made up of calcium and phosphate and is best characterized as a poorly crystalline hydroxyapatite. The mineral phase of bone is deposited initially in intimate relation to the collagen fibrils and is found in specific locations in the “holes” between the collagen fibrils. This architectural arrangement of mineral and matrix results in a two-phase material well suited to withstand mechanical stresses. The organization of collagen influences the amount and type of mineral phase formed in bone. Although the primary structures of type I collagen in skin and bone tissues are similar, there are differences in posttranslational modifications and distribution of intermolecular cross-links. The holes in the packing structure of the collagen are larger in mineralized collagen of bone and dentin than in unmineralized collagens such as those in tendon. Single amino acid substitutions in the helical portion of either the α1 (COL1A1) or α2 (COL1A2) chains of type I collagen disrupt the organization of bone in osteogenesis imperfecta. The severe skeletal fragility associated with this group of disorders highlights the importance of the fibrillar matrix in the structure of bone (Chap. 363).
Osteoblasts synthesize and secrete the organic matrix. They are derived from cells of mesenchymal origin (Fig. 352-1A). Active osteoblasts are found on the surface of newly forming bone. As an osteoblast secretes matrix, which then is mineralized, the cell becomes an osteocyte, still connected with its blood supply through a series of canaliculi. Osteocytes account for the vast majority of the cells in bone. They are thought to be the mechanosensors in bone that communicate signals to surface osteoblasts and their progenitors through the canalicular network and thereby serve as master regulators of bone formation and resorption. Remarkably, osteocytes also secrete fibroblast growth factor 23 (FGF23), a major regulator of phosphate metabolism (see below). Mineralization of the matrix, both in trabecular bone and in osteones of compact cortical bone (Haversian systems), begins soon after the matrix is secreted (primary mineralization) but is not completed for several weeks or even longer (secondary mineralization). Although this mineralization takes advantage of the high concentrations of calcium and phosphate, already near saturation in serum, mineralization is a carefully regulated process that is dependent on the activity of osteoblast-derived alkaline phosphatase, which probably works by hydrolyzing inhibitors of mineralization.
Pathways regulating development of A. osteoblasts and B. osteoclasts. Hormones, cytokines, and growth factors that control cell proliferation and differentiation are shown above the arrows. Transcription factors and other markers specific for various stages of development are depicted below the arrows. BMPs, bone morphogenic proteins; wnts, wingless-type mouse mammary tumor virus integration site; PTH, parathyroid hormone; Vit D, vitamin D; IGFs, insulin-like growth factors; Runx2, Runt-related transcription factor 2; M-CSF, macrophage colony-stimulating factor; PU-1, a monocyte- and B lymphocyte–specific ets family transcription factor; NFκB, nuclear factor κB; TRAF, tumor necrosis factor receptor–associated factors; RANK ligand, receptor activator of NFκB ligand; IL-1, interleukin 1; IL-6, interleukin 6. (Modified from T Suda et al: Endocr Rev 20:345, 1999, with permission.)
Genetic studies in humans and mice have identified several key genes that control osteoblast development. Runx2 is a transcription factor expressed specifically in chondrocyte (cartilage cells) and osteoblast progenitors as well as in hypertrophic chondrocytes and mature osteoblasts. Runx2 regulates the expression of several important osteoblast proteins, including osterix (another transcription factor needed for osteoblast maturation), osteopontin, bone sialoprotein, type I collagen, osteocalcin, and receptor-activator of NFκB (RANK) ligand. Runx2 expression is regulated in part by bone morphogenic proteins (BMPs). Runx2-deficient mice are devoid of osteoblasts, whereas mice with a deletion of only one allele (Runx2 +/−) exhibit a delay in formation of the clavicles and some cranial bones. The latter abnormalities are similar to those in the human disorder cleidocranial dysplasia, which is also caused by heterozygous inactivating mutations in Runx2.
The paracrine signaling molecule, Indian hedgehog (Ihh), also plays a critical role in osteoblast development, as evidenced by Ihh-deficient mice that lack osteoblasts in bone formed on a cartilage mold (endochondral ossification). Signals originating from members of the wnt (wingless-type mouse mammary tumor virus integration site) family of paracrine factors are also important for osteoblast proliferation and differentiation. Numerous other growth-regulatory factors affect osteoblast function, including the three closely related transforming growth factor βs, fibroblast growth factors (FGFs) 2 and 18, platelet-derived growth factor, and insulin-like growth factors (IGFs) I and II. Hormones such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] activate receptors expressed by osteoblasts to assure mineral homeostasis and ...