Recent advances in bone biology provide insight into the pathogenesis of bone diseases

Bone is modeled during embryonic development by endochondral and membranous ossification and is continuously remodeled thereafter under the influence of local and systemic factors to provide structural support and assist in c alcium homeostasis. Recent studies of knockout and transgenic mice have inc reased understanding of the regulation of bone modeling during development and of remodeling of mature bone and have shed new light on the pathogenesi s of a number of bone disorders. For example, fibroblast growth factor rece ptor-3, parathyroid hormone-related protein, and tartrate-resistant acid ph osphatase affect the function of chondrocytes during endochondral ossificat ion (the latter two by regulating their life spans and thus growth plate th ickness and bone length). Some ubiquitously expressed genes seem unexpected ly to have unique functions that are largely confined to bone cells: M-CSF, C-Fos, PU.1, and NF-kappa B are required for osteoclast formation, whereas c-Src and Mitf (microphthalmia transcription factor) are required for oste oclast activity after the cells have formed. Knockout of these genes result s in osteopetrosis, a disorder characterized by persistence in marrow cavit ies of unresorbed osteocartilaginous matrix and, as in some affected humans , by increased mortality. Some proteins seem to act as negative regulators of bone cell function, for example osteoprotegerin (a soluble TNF receptor) in osteoclasts; osteocalcin, bone sialoprotein, and 5-lipoxygenase in oste oblasts. Regulation of osteoclast life span may be an important mechanism b y which estrogen and bisphosphonates prevent bone loss in conditions charac terized by increased bone resorption, such as postmenopausal osteoporosis. The unique requirement of bone cells for certain gene products raises the p ossibility that these cells may have specific responses to inhibitory or st imulatory agents, and that signaling molecules in these response pathways c ould be specific targets for novel therapies to treat or prevent common bon e diseases.