The origin of osteoclasts: evidence, clinical implications and investigative challenges of an extra-skeletal source

Recent evidence for an extraskeletal origin of osteoclasts and the historical record of the genesis of osteoclasts are examined critically. Reviews of the structure, function and development of osteoclasts from mononuclear precursors, the local regulation of bone resorption and the coupling of bone formation to preceding resorption are presented as a background for discussing the clinical implications for management of osteolytic bone diseases. The roles of osteoclasts and macrophages as phagocytes are compared and contrasted, and recent evidence for macrophage heterogeneity resulting from site-specific monoblastic precursors is reviewed. The implications of these recent developments in macrophage biology are extrapolated to osteoclasts and the existence of site-specific, extraskeletal osteoclast precursors is proposed. Finally, the investigative challenges inherent in these perspectives are discussed.