Chapter 12 - Regulating Bone Resorption: Targeting Integrins, Calcitonin Receptor, and Cathepsin K

Abstract

Skeletal growth and repair during adult life occurs via bone remodeling, a coordinated and tightly regulated process. The maintenance of normal bone mass depends on maintaining the appropriate balance between bone formation and bone resorption. The processes of bone resorption and formation are tightly coupled, so that a change in either usually leads to a subsequent compensating change in the other. Bone resorption is carried out by osteoclasts, which are multinucleated, terminally differentiated cells derived from the monocyte/macrophage lineage. The rate of bone resorption varies as a function of changes in both the number and activity of osteoclasts, the only cells capable of resorbing bone. Osteoclastogenesis is controlled by the proliferation and homing of the progenitors to bone and their differentiation and fusion to form multinucleated cells. Osteoclastic bone resorption is a process requiring physical intimacy between resorptive cell and bone matrix. Thus, cell matrix attachment molecules, particularly integrins, play a central role in the capacity of osteoclasts to degrade bone. Because of its potent inhibitory effects on osteoclast activity, calcitonin has long been recognized as a potential therapeutic agent for the treatment of diseases that are characterized by increased bone resorption, such as osteoporosis, Paget's disease, and late-stage malignancies. Finally, cathepsins participate in important physiological as well as pathological processes, including activation of precursor proteins (proenzymes and prohormones), bone remodeling, MHC-II-mediated antigen presentation, keratinocyte differentiation, hair cycle morphogenesis, and apoptosis. They have also been implicated in tumor progression and metastasis, inflammatory diseases, arthrosclerosis, and periodontitis.