Lkt

Osteoclasts

Osteoclasts on the bone surface resorbing old bone

Osteoid becoming mineralized

Macrophages

Osteoclasts

Macrophages

Osteoclasts on the bone surface resorbing old bone

Macrophages phagocytose the matrix debris

Mesenchymal stem cell

Macrophages phagocytose the matrix debris

Mesenchymal stem cell

Osteoblasts filling the resorption cavity with osteoid

Osteoblasts appearing at the resorption site

FIGURE 9-13 Schematic model of a bone remodeling unit; see also Table 9-6. In this model, the initiation of the remodeling event occurs through activation of the osteoclast. The osteoclast is believed to attach its ruffled border to the bone surface in order to carry out its biological actions in a defined local environment. The osteoclast then actively resorbs bone locally as a consequence of local acidification; the resulting mobilized Ca2+ is then directed to the blood compartment. Also, the osteoclast secretes proteases that locally digest the bone matrix proteins (collagen and osteocalcin). Next macrophages phagocytose the matrix debris; the net result is the creation of a local bone pit that can be viewed under the microscope. Then in a reversal phase, the osteoblasts move to the resorbed area and, under suitable hormonal activation, biosynthesize new extracellular matrix proteins followed by the orderly importation of Ca2+ and Pi to create the mineral phase. Thus, the resorption cavity has become filled with new hydroxyapatite. The process culminates in the conversion of the active osteoblasts to lining cells, which cover the quiescent bone surface. Linked to this remodeling event, of necessity, is the orderly generation via cell differentiation of the necessary numbers of osteoclasts and osteoblasts. Osteoblasts are ultimately derived from mesenchymal stem cells and are more immediately derived from osteoprogenitor cells. Osteoclasts are ultimately derived from a hematopoietic stem cell, which, under the influence of la,25(OH)2D3 and other cytokines, differentiates to yield functional osteoclasts (see Figure 9-12) Adapted by permission of Manolagas, S. C., and Jilka, R. L. (1975). New Engl. J. Med. 332, 305-311.

cyte > monocyte s=> macrophage. Macrophages are believed to be precursors of osteoclasts, the cells responsible for bone resorption. Further, y-interferon derived from activated T lymphocytes will induce bone marrow macrophages to biosynthesize small amounts of la,25(OH)2D3. Thus, there is a paracrine system operative for la,25(OH)2D3, such that "locally" produced l«,25(OH)2D3 in the bone marrow acts on neighboring cells to promote differentiation toward macrophages and osteoclasts, thereby increasing the bone calcium resorption capability.

E. Biology of Bone Remodeling

Bone is a metabolically active organ, undergoing throughout life a continual turnover and remodeling process involving bone resorption and accretion. The balance between the rates of bone resorption and bone formation will determine, both at a local level or globally (the entire skeleton), whether there is a negative, neutral, or positive calcium balance. The biological activities of bone cells are subject to the actions of a multitude of hormones, cytokines, and other physiological regulators (see Table 9-5).

9. Calcium-Regulating Hormones TABLE 9-6 Steps of Bone Remodeling

Cell or cellular event

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Cure Tennis Elbow Without Surgery

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