Chapter 13 : Osteoclasts—Key Players in Skeletal Health and Disease

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Although bone is one of the hardest tissues in the body, necessary for its structural and protective roles, this organ is not static. Bone matrix must be renewed over time in order to maintain its mechanical properties, and myeloid lineage cells called osteoclasts (OCs) are the specialized cells that perform this critical function. Since bone is the major storage site for calcium, OCs play an important role in the regulation of this signaling ion by releasing it from bone. In this process, OCs respond indirectly to calcium-regulating hormones such as parathyroid hormone and 1,25(OH) vitamin D. Growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor β (TGF-β) are also incorporated into bone matrix and released by OCs, affecting the coupling of bone formation to bone resorption and potentially targeting other cells in the microenvironment, such as metastatic tumors. Lastly, OCs retain features of other myeloid cells, such as antigen presentation and cytokine production, which afford them the potential to affect immune responses. Thus, the OC plays many roles in health and disease.

Citation: Novack D, Mbalaviele G. 2017. Osteoclasts—Key Players in Skeletal Health and Disease, p 235-255. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0011-2015
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Figure 1

A model of OC differentiation. OCs differentiate from HSCs. The hematopoietic niche comprises endothelial cells and perivascular stromal cells, which exhibit mesenchymal stem cell (MSC) features. It is still unclear whether OC precursors directly differentiate into OCs or enter the bloodstream before reentering the bone microenvironment to form OCs. In any scenario, higher levels of chemoattractants toward bone surfaces, including bone ECM proteins, lipid mediators (e.g., sphingosine-1-phosphate), and ECM degradation products, create gradients that attract OC precursors to the hard tissue, where they fuse and complete the differentiation process. Conversely, higher levels of perivascular chemorepellents (not drawn for simplicity) may also contribute to the migration of OC precursors toward the endosteum.

Citation: Novack D, Mbalaviele G. 2017. Osteoclasts—Key Players in Skeletal Health and Disease, p 235-255. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0011-2015
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Image of Figure 2
Figure 2

Key molecules involved in OC function. Loss of function of any of the depicted molecules causes osteopetrosis due to defective OC activity. OCs adhere to bone matrix proteins via integrin αβ and are polarized such that the plasma membrane-facing bone is convoluted (ruffled) and contains the proton pump (v-ATPase) and Cl channel 7 (ClC7), whereas the basolateral membrane bears the HCO /Cl antiporter. Cytoplasmic carbonic anhydrase type II (CAII) generates the protons to be secreted into the resorption lacuna beneath the cell. This lacuna becomes isolated from the rest of the extracellular space by the tight adhesion of αβ to the bone surface at the sealing zone. The cytoplasmic domain of β recruits signaling proteins, which induce the association of actin with interacting partners (including talin, vinculin, kindlin, myosin IIA, and paxillin) and formation of an actin ring that defines the periphery of the ruffled membrane. Concerted action of ClC7 and v-ATPase produces a high concentration of HCl that acidifies the resorption lacuna, leading to the dissolution of the inorganic components of the bone matrix. Acidified cytoplasmic vesicles containing lysosomal enzymes such as cathepsin K (Cat K) are also transported toward the bone-apposed plasma membrane and, ultimately, the sealed resorption lacuna, where they digest the exposed matrix proteins.

Citation: Novack D, Mbalaviele G. 2017. Osteoclasts—Key Players in Skeletal Health and Disease, p 235-255. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0011-2015
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