Understanding osteoclast formation and function: implications for future therapies for osteoporosis

Abstract

Purpose of review: The authors summarize recent strategic insights into the mechanisms that underlie osteoclast formation, function, and survival, and explore and analyze possible therapeutic implications. Bone loss can be the result of relative or absolute increases in osteoclastogenesis or osteoclast function, which accordingly offer natural targets for therapeutic maneuvers. Recent findings: The recent introduction of molecular tools for the study of stem cell differentiation, osteoclast culture, osteoclast signaling mechanisms, and transgenic animals offers insights into such opportunities, which are discussed along the following lines. First, obligatory signaling systems are required for osteoclast determination and development from hematopoietic stem cell precursors, of which the most notable involve the receptor activator for nuclear-factor κB (RANK) signaling system. Second, modulatory rather than obligatory agents, including some cytokines and estrogen, have an established or potential clinical use. Third, cell physiologic processes of polarization to form ruffled membranes, bone matrix adhesion, and acid and protease secretion into the resorptive hemivacuole offer further opportunities for drug targeting. Fourth, there are both the local feedback regulatory mechanisms that detect extracellular Ca2+ changes and the systemic regulatory mechanisms involving the hormone calcitonin. Lastly, there are recent important developments in bisphosphonate therapy that remain of primary importance for osteoporosis management in humans. Summary: The authors argue that the recent clarification of both osteoclastogenesis, the major functional specializations required for osteoclastic bone resorption, and of some of their associated, highly expressed proteins provide potential therapeutic targets that may modify bone degradation usefully in attempts to relate basic and translational issues to future antiresorptive therapies.