Abstract
Osteoclasts (OCs) are bone-resorbing cells that originate from hematopoietic stem cells and develop through the fusion of mononuclear myeloid precursors. Dysregulation of OC development causes bone disorders such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Although the molecular mechanisms underlying osteoclastogenesis have been well established, the means by which OCs maintain their survival during OC development remain unknown. We found that Ninjurin1 (Ninj1) expression is dynamically regulated during osteoclastogenesis and that Ninj1−/− mice exhibit increased trabecular bone volume owing to impaired OC development. Ninj1 deficiency did not alter OC differentiation, transmigration, fusion, or actin ring formation but increased Caspase-9-dependent intrinsic apoptosis in prefusion OCs (preOCs). Overexpression of Ninj1 enhanced the survival of mouse macrophage/preOC RAW264.7 cells in osteoclastogenic culture, suggesting that Ninj1 is important for the survival of preOCs. Finally, analysis of publicly available microarray data sets revealed a potent correlation between high NINJ1 expression and destructive bone disorders in humans. Our data indicate that Ninj1 plays an important role in bone homeostasis by enhancing the survival of preOCs.
Highlights
Bone is a dynamic tissue maintained by continuous remodeling dependent upon the balance between bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs)[1]
OC differentiation is mediated by two essential cytokines, macrophage colonystimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL), produced by OBs, stromal cells, and T lymphocytes[3]
Our findings suggest that Ninj[1] has a novel role in OC development and bone homeostasis and might represent a potent therapeutic target for destructive bone disorders
Summary
Bone is a dynamic tissue maintained by continuous remodeling dependent upon the balance between bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs)[1]. OC differentiation is mediated by two essential cytokines, macrophage colonystimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL), produced by OBs, stromal cells, and T lymphocytes[3]. M-CSF sustains the survival of OC precursors and mature OCs, and RANKL promotes OC differentiation via the induction of NFATc1, a master transcription factor of osteoclastogenesis, including differentiation, fusion, maturation, activation, and survival[2,3,4,5]. OCs exhibit unique morphological features, such as multinucleation, which is accomplished by the fusion of mononuclear OC precursor cells, and an actin ring cytoskeleton composed of podosome belts[6,7]. Fine movements and well-organized actin ring cytoskeletons are prerequisites for cell–cell fusion and for OC resorptive function[7]. Dysregulation of OC development and/or function leads to pathological bone disorders, such as osteopetrosis, Paget’s disease, rheumatoid arthritis, and postmenopausal osteoporosis[8,9,10,11]
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