Abstract
Cytoskeleton organization and lysosome secretion play an essential role in osteoclastogenesis and bone resorption. The cytoplasmic dynein is a molecular motor complex that regulates microtubule dynamics and transportation of cargos/organelles, including lysosomes along the microtubules. LIS1, NDE1, and NDEL1 belong to an evolutionary conserved pathway that regulates dynein functions. Disruption of the cytoplasmic dynein complex and deletion of LIS1 in osteoclast precursors arrest osteoclastogenesis. Nonetheless, the role of NDE1 and NDEL1 in osteoclast biology remains elusive. In this study, we found that knocking-down Nde1 expression by lentiviral transduction of specific shRNAs markedly inhibited osteoclastogenesis in vitro by attenuating the proliferation, survival, and differentiation of osteoclast precursor cells via suppression of signaling pathways downstream of M-CSF and RANKL as well as osteoclast differentiation transcription factor NFATc1. To dissect how NDEL1 regulates osteoclasts and bone homeostasis, we generated Ndel1 conditional knockout mice in myeloid osteoclast precursors (Ndel1ΔlysM) by crossing Ndel1-floxed mice with LysM-Cre mice on C57BL/6J background. The Ndel1ΔlysM mice developed normally. The µCT analysis of distal femurs and in vitro osteoclast differentiation and functional assays in cultures unveiled the similar bone mass in both trabecular and cortical bone compartments as well as intact osteoclastogenesis, cytoskeleton organization, and bone resorption in Ndel1ΔlysM mice and cultures. Therefore, our results reveal a novel role of NDE1 in regulation of osteoclastogenesis and demonstrate that NDEL1 is dispensable for osteoclast differentiation and function.
Highlights
Introduction published maps and institutional affilMaintenance of skeletal integrity and strength is a tightly regulated process of continuous bone remodeling orchestrated by a closely balanced interplay between bone-resorbing osteoclasts and bone-forming osteoblasts [1,2]
To elucidate the role of NDE1 in osteoclast differentiation and function, we knocked down Nde1 expression by lentivirus-mediated transduction of two Nde1-specific shRNAs in wildtype bone marrow monocytes (BMMs)
To elucidate the role of NDE1 in osteoclast differentiation and function, we knocked down Nde1 expression by lentivirus‐mediated transduction of two Nde1‐specific shRNAs in wildtype bone marrow monocytes (BMMs)
Summary
Maintenance of skeletal integrity and strength is a tightly regulated process of continuous bone remodeling orchestrated by a closely balanced interplay between bone-resorbing osteoclasts and bone-forming osteoblasts [1,2]. Abnormal bone resorption due to increased or decreased osteoclast number/activity is associated with multiple pathological skeleton conditions, including osteoporosis, rheumatoid arthritis, Paget’s disease of bone, and osteopetrosis [3]. Deciphering the mechanisms that regulate osteoclast differentiation and function will lay new insights into osteoclast biology and significantly improve our understanding and treatment of metabolic bone diseases. Osteoclasts are multinucleated hematopoietic lineage cells derived from fusion of mononuclear precursors of the monocyte/macrophage family [4,5]. Osteoclastogenesis in vivo and in vitro is triggered by two key cytokines, M-CSF (macrophage colonystimulating factor) and RANKL (receptor activator of nuclear factor-kB ligand).
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