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Abstract
BackgroundOsteoclasts (OCs) are motile multinucleated cells derived from differentiation and fusion of hematopoietic progenitors of the monocyte-macrophage lineage that undergo a multistep process called osteoclastogenesis. The biological function of OCs is to resorb bone matrix for controlling bone strength and integrity, which is essential for bone development. The bone resorption function is based on the remodelling of the actin cytoskeleton into an F-actin-rich structure known as the sealing zone for bone anchoring and matrix degradation. Non-muscle caldesmon (l-CaD) is known to participate in the regulation of actin cytoskeletal remodeling, but its function in osteoclastogenesis remains unclear.Methods/resultsIn this study, gain and loss of the l-CaD level in RAW264.7 murine macrophages followed by RANKL induction was used as an experimental approach to examine the involvement of l-CaD in the control of cell fusion into multinucleated OCs in osteoclastogenesis. In comparison with controls, l-CaD overexpression significantly increased TRAP activity, actin ring structure and mineral substrate resorption in RANKL-induced cells. In contrast, gene silencing against l-CaD decreased the potential for RANKL-induced osteoclastogenesis and mineral substrate resorption. In addition, OC precursor cells with l-CaD overexpression and gene silencing followed by RANKL induction caused 13% increase and 24% decrease, respectively, in cell fusion index. To further understand the mechanistic action of l-CaD in the modulation of OC fusion, atomic force microscopy was used to resolve the mechanical changes of cell spreading and adhesion force in RANKL-induced cells with and without l-CaD overexpression or gene silencing.Conclusionsl-CaD plays a key role in the regulation of actin cytoskeletal remodeling for the formation of actin ring structure at the cell periphery, which may in turn alter the mechanical property of cell-spreading and cell surface adhesion force, thereby facilitating cell-cell fusion into multinucleated OCs during osteoclastogenesis.
Highlights
Osteoclasts (OCs) are motile multinucleated cells derived from differentiation and fusion of hematopoietic progenitors of the monocyte-macrophage lineage that undergo a multistep process called osteoclastogenesis
L-CaD is associated with the formation of actin ring in RANKL-induced osteoclastogenesis During RANKL-induced differentiation, RAW264.7 cells undergo characteristic changes of increased cell-cell fusion into large and multinucleated tartrate resistant alkaline phosphatase (TRAP)-positive OCs (Fig. 1a)
L-CaD expression levels modified the actin ring structures in OCs and their mineralized matrix degradation To determine the role of l-CaD in forming actin ring structures in OCs, gain- and loss-of-functions in RAW264.7 cells overexpressing l-CaD (Supplementary S2) and treated with si l-CaD (Additional file 1: Figure S1), respectively, followed by RANKL induction were used
Summary
Osteoclasts (OCs) are motile multinucleated cells derived from differentiation and fusion of hematopoietic progenitors of the monocyte-macrophage lineage that undergo a multistep process called osteoclastogenesis. The bone resorption function is based on the remodelling of the actin cytoskeleton into an F-actin-rich structure known as the sealing zone for bone anchoring and matrix degradation. Osteoclasts (OCs) are multinucleated, bone-resorbing cells that differentiate from hematopoietic progenitors of the monocyte-macrophage lineage through a multistep process called osteoclastogenesis, including cell commitment, cell-cell fusion, and maturation [1, 2]. The activation for c-Src and the downstream kinases induces the formation of the actin-rich structures known as podosomes [4]. Because OCs are key players for bone resorption, they are one of the main targets for treatment of osteoporosis based on the critical events of podosome formation in osteoclastogenesis [8, 9]
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