| 研究実績の概要 |
- CCR5 deficiency impairs osteoclast adhesion; Ccr5-deficient osteoclasts showed decreased bone resorption activity accompanied with disorganized cellular architecture and impaired motility. Multimodal and multidimensional super-resolution microscopy facilitates to observe irregular microtubule network and podosome arrangement in Ccr5-/- osteoclasts, suggesting malfunctions for cell polarity, cell adhesion and locomotion. Time-lapse imaging and subsequent numerical analysis of cell deformity index revealed that Ccr5-deficient osteoclasts reduced their stability of attachment to matrix as evidence by abnormal motility.
- CCR5-mediated signals involved in Focal adhesion complex and its downstream signals; Expression of integrins and signaling of FAK-Src complex were markedly reduced in Ccr5-deficient osteoclasts, which was concomitant to reduced activity of small GTPase. CCL5, a major ligand of CCR5, stimulated FAK phosphorylation not Src in wild type osteoclasts. RANKL-induced Src phosphorylation and downstream signals were enhanced by CCL5 stimuli, suggesting a cooperative role of CCR5-mediated signaling with RANKL-mediated signaling pathways. Forced expression of constitutive active forms of Rho and Rac in Ccr5-deficient osteoclasts rescued integrin expression and bone resorption. These findings suggested that CCR5-mediated signaling, with cooperating with RANKL-mediated signaling, regulate small GTPases, and thus cellular architecture and motility of differentiated osteoclasts.
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