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 2þ -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 Ca 2þ , which in turn activates calmodulin and its downstream effectors. In particular, the Ca 2þ /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 2þ /calmodulin-regulated effector protein, CaMKII, is also involved. CaMKII þ/À 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.

TLR-Mediated Secretion of Endoplasmic Reticulum Aminopeptidase 1 from Macrophages

“…Elevation of intracellular Ca 2+ levels causes calmodulin activation, which is critical in various signal transduction systems (27,(31)(32)(33); therefore, we next examined the correlation between calmodulin activation and ERAP1 secretion to test the possible involvement of calmodulin in the secretion process. As shown in Fig.…”

Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

“…Celastrol is an antioxidant and anti-inflammatory agent that has been suggested for use in treating Alzheimer disease, which prematurely affects many DS patients (22). Calmidazolium is a calmodulin inhibitor, which decreases sensitivity to calcium ion signaling, and has been considered for use in treating osteoporosis (23). Verapamil and felodipine are both calcium channel blockers, whereas dimethyloxalylglycine is a hydroxylase inhibitor thought to increase resistance to oxidative stress (24,25).…”

Adenylate cyclase and calmodulin-dependent kinase have opposite effects on osteoclastogenesis by regulating the PKA-NFATc1 pathway

“…(13,14) It was shown previously that Ca 2þ -activated CaMKII and CaMKIV enhance the expression of NFATc1 through c-Fos induction in osteoclasts. (15)(16)(17) phosphodiesterases (PDEs). One soluble isoform and nine membrane-bound AC isoforms that have distinct patterns of responses to Ca 2þ /CaM and protein kinases have been identified.…”