ADP-Ribosylation Factor 1 Regulates Proliferation, Migration, and Fusion in Early Stage of Osteoclast Differentiation.

Min Kim,Soo Lee,Dong Gu,Seoung Lee,Daewon Jeong,Hyunsoo Kim,Kyunghee Lee

doi:10.3390/ijms161226168

Abstract

Small G-protein adenosine diphosphate (ADP)-ribosylation factors (ARFs) regulate a variety of cellular functions, including actin cytoskeleton remodeling, plasma membrane reorganization, and vesicular transport. Here, we propose the functional roles of ARF1 in multiple stages of osteoclast differentiation. ARF1 was upregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and transiently activated in an initial stage of their differentiation. Differentiation of ARF1-deficient osteoclast precursors into mature osteoclasts temporarily increased in pre-maturation stage of osteoclasts followed by reduced formation of mature osteoclasts, indicating that ARF1 regulates the osteoclastogenic process. ARF1 deficiency resulted in reduced osteoclast precursor proliferation and migration as well as increasing cell-cell fusion. In addition, ARF1 silencing downregulated c-Jun N-terminal kinase (JNK), Akt, osteopontin, and macrophage colony-stimulating factor (M-CSF)-receptor c-Fms as well as upregulating several fusion-related genes including CD44, CD47, E-cadherin, and meltrin-α. Collectively, we showed that ARF1 stimulated proliferation and migration of osteoclast precursors while suppressing their fusion, suggesting that ARF1 may be a plausible inter-player that mediates the transition to osteoclast fusion at multiple steps during osteoclast differentiation

Highlights

Bone remodeling is an active and dynamic process that involves the coordinated actions of bone formation by osteoblasts and bone resorption by osteoclasts
ARF1 has well documented to play a crucial role in the vesicle-mediated transport, functioning as an important precursor proliferation and migration when compared with control cells
We suggest that changes in the level of macrophage colony-stimulating factor (M-CSF) receptor c-Fms and receptor activator of nuclear factor kappa-B ligand (RANKL) receptor RANK in ARF1-deficient cells may have resulted from ARF1-mediated alterations of cell surface expression of the receptors

Summary

Introduction

Bone remodeling is an active and dynamic process that involves the coordinated actions of bone formation by osteoblasts and bone resorption by osteoclasts. Osteoclastogenesis reportedly involves a series of regulatory steps such as proliferation and survival of progenitors, differentiation into mononuclear pre-osteoclasts, fusion into mature multinucleated osteoclasts, and activation of osteoclastic bone resorption [1]. The earliest event of osteoclastogenesis is hematopoietic stem cell commitment to the monocyte/macrophage lineage by the transcription factor PU., which induces expression of c-Fms, a receptor for M-CSF [2,3]. In the osteoclast precursor stage, activation of M-CSF/c-Fms signaling promotes proliferation of bone marrow-derived macrophages (BMMs), which are osteoclast precursors [1,4]. RANKL activates nuclear factor of activated T-cells c1 (NFATc1), a master regulator of osteoclast development, through calcium signaling [9,10]. Among multiple steps during osteoclast differentiation, osteoclast precursor fusion is a complicated process including cell adherence to the bone surface, migration, and cell-cell contact as well as being an essential step in forming multinucleated mature osteoclasts via induction of a fusion-competent state [11]

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Results

Conclusion