title: Calmodulin is a critical regulator of osteoclastic differentiation, function, and survival.
abstract: Increased osteoclastic resorption and subsequent bone loss are common features of many debilitating diseases including osteoporosis, bone metastases, Paget's disease, and rheumatoid arthritis. While rapid progress has been made in elucidating the signaling pathways directing osteoclast differentiation and function, a comprehensive picture is far from complete. Here, we explore the role of the Ca(2+)-activated regulator calmodulin in osteoclastic differentiation, functional bone resorption, and apoptosis. During active bone resorption, calmodulin expression is increased, and calmodulin concentrates at the ruffled border, the organelle utilized for acid transport and bone dissolution. Pharmacologic inhibitors of calmodulin, several of which are already used clinically as anti-cancer and anti-psychotic agents, inhibit osteoclastic acid transport, suggesting their potential as bone-sparing drugs. Recent studies also implicate calmodulin in osteoclast apoptosis through a mechanism involving its direct interaction with the death receptor Fas. During osteoclastogenesis, RANKL-induction stimulates a rise in intracellular Ca2+, which in turn activates calmodulin and its downstream effectors. In particular, the Ca(2+)/calmodulin-dependent phosphatase calcineurin and its targets, the NFAT family of transcription factors, have been posited as the master regulators of osteoclastogenesis. However, recent in vivo and in vitro studies demonstrate that another Ca(2+)/calmodulin-regulated effector protein, CaMKII, is also involved. CaMKII(+/-) mutant mice have reduced osteoclast numbers, and CaMKII antagonists inhibit osteoclastogenesis in vitro. Furthermore, CaMKII is known to activate AP-1 transcription factors, which are also required for RANKL-induced osteoclast gene transcription, and recent findings suggest that CaMKII can down-regulate gp130, a cytokine receptor involved in bone remodeling and implicated in numerous osteo-articular diseases.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, 619, 19th Street South, West Pavilion 220, Birmingham, AL 35233-7331, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Seales
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Micoli
authors.forename: Jay M
authors.initials: JM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D017209:Apoptosis; D001862:Bone Resorption; D020013:Calcium Signaling; D002147:Calmodulin / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
chemical_list: D002147:Calmodulin; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor