Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute (DRI), School of Dentistry, Seoul National University, Seoul 03080, Korea.
Mol Cells. 2022 Oct 31;45(10):749-760. doi: 10.14348/molcells.2022.0058. Epub 2022 Aug 29.
Osteoclast generation from monocyte/macrophage lineage precursor cells needs to be tightly regulated to maintain bone homeostasis and is frequently over-activated in inflammatory conditions. PARK2, a protein associated with Parkinson's disease, plays an important role in mitophagy via its ubiquitin ligase function. In this study, we investigated whether PARK2 is involved in osteoclastogenesis. PARK2 expression was found to be increased during the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. PARK2 gene silencing with siRNA significantly reduced osteoclastogenesis induced by RANKL, LPS (lipopolysaccharide), TNFα (tumor necrosis factor α), and IL-1β (interleukin-1β). On the other hand, overexpression of PARK2 promoted osteoclastogenesis. This regulation of osteoclastogenesis by PARK2 was mediated by IKK (inhibitory κB kinase) and NF-κB activation while MAPK (mitogen-activated protein kinases) activation was not involved. Additionally, administration of PARK2 siRNA significantly reduced osteoclastogenesis and bone loss in an model of inflammatory bone erosion. Taken together, this study establishes a novel role for PARK2 as a positive regulator in osteoclast differentiation and inflammatory bone destruction.
破骨细胞由单核细胞/巨噬细胞系前体细胞生成，其生成需要受到严格调控，以维持骨内稳态，而在炎症条件下通常会过度激活。PARK2 是一种与帕金森病相关的蛋白，其通过泛素连接酶功能在细胞自噬中发挥重要作用。在本研究中，我们研究了 PARK2 是否参与破骨细胞生成。研究发现，在核因子-κB 配体（RANKL）诱导的破骨细胞分化过程中，PARK2 的表达增加。用 siRNA 沉默 PARK2 基因可显著减少由 RANKL、LPS（脂多糖）、TNFα（肿瘤坏死因子 α）和 IL-1β（白细胞介素-1β）诱导的破骨细胞生成。另一方面，过表达 PARK2 可促进破骨细胞生成。PARK2 对破骨细胞生成的这种调节是通过 IKK（抑制κB 激酶）和 NF-κB 激活介导的，而 MAPK（丝裂原活化蛋白激酶）激活则不参与。此外，给予 PARK2 siRNA 可显著减少炎症性骨侵蚀模型中的破骨细胞生成和骨丢失。综上所述，本研究确立了 PARK2 作为破骨细胞分化和炎症性骨破坏的正向调节因子的新作用。
