Mdivi-1 Inhibits Pink1/Parkin-Dependent Mitophagy To Alleviate Osteolysis

Wear particle-induced aseptic craniofacial osteolysis around the implant-bone interface affects the prognosis of various implants. This study aims to explore the effects of the PINK1/Parkin pathway involved in mitochondrial quality control and its inhibitor Mdivi-1 on osteoclast-mediated physiological bone homeostasis and their therapeutic potential for craniofacial osteolysis. Myeloid-specific Parkin knockout mice (LysM-Cre/Park2flox/flox; Park2ΔM/ΔM) were generated, and Park2ΔM/ΔM macrophages were isolated for RANKL-induced osteoclast differentiation. The differentiation and function of Park2ΔM/ΔM osteoclasts were further evaluated, while PINK1 expression was detected by Western blot. Mdivi-1 was applied to RANKL-induced wild-type bone marrow-derived macrophages, followed by osteoclast activity evaluated via TRAP staining, F-actin staining and bone resorption assays. An aseptic craniofacial osteolysis model was established by titanium particle injection into wild-type male mouse calvaria, with bone mass analysis via Micro-CT and histomorphometric (H&E/TRAP staining). Upon osteoclastogenic induction, Park2ΔM/ΔM macrophages retained normal RANKL-induced osteoclast differentiation, accompanied by compensatory PINK1 upregulation. Mdivi-1 significantly inhibited both PINK1 and Parkin protein expression, attenuating osteoclastogenesis concentration-dependently. In vivo, Mdivi-1 effectively alleviated titanium particle-induced bone resorption and trabecular structure destruction and blocked osteoclast accumulation at the lesion sites. While myeloid-specific Park2 deletion preserves osteoclast differentiation and bone homeostasis in mice probably due to PINK1 compensation, Mdivi-1 as the inhibitor of PINK1/Parkin-dependent mitophagy may provide a novel therapeutic strategy towards aseptic craniofacial osteolysis.