Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Orthopaedic Surgery, The Xiangya Hospital of Central South University, Changsha, China.
JCI Insight. 2020 Apr 23;5(8):135446. doi: 10.1172/jci.insight.135446.
Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However, the mechanisms that initiate subchondral bone angiogenesis remain unclear. We show that abnormally increased platelet-derived growth factor-BB (PDGF-BB) secretion by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to osteoarthritis development. In mice after destabilization of the medial meniscus (DMM), aberrant joint subchondral bone angiogenesis developed during an early stage of osteoarthritis, before articular cartilage damage occurred. Mononuclear preosteoclasts in subchondral bone secrete excessive amounts of PDGF-BB, which activates platelet-derived growth factor receptor-β (PDGFR-β) signaling in pericytes for neo-vessel formation. Selective knockout of PDGF-BB in preosteoclasts attenuates subchondral bone angiogenesis and abrogates joint degeneration and subchondral innervation induced by DMM. Transgenic mice that express PDGF-BB in preosteoclasts recapitulate pathological subchondral bone angiogenesis and develop joint degeneration and subchondral innervation spontaneously. Our study provides the first evidence to our knowledge that PDGF-BB derived from preosteoclasts is a key driver of pathological subchondral bone angiogenesis during osteoarthritis development and offers a new avenue for developing early treatments for this disease.
破骨前体细胞异常增加血小板衍生生长因子-BB（PDGF-BB）的分泌可诱导软骨下骨血管生成，从而促进骨关节炎的发生。在半月板内侧稳定术（DMM）后的小鼠中，在关节软骨损伤发生之前，骨关节炎的早期就出现了异常的关节软骨下骨血管生成。软骨下骨中的单核破骨前体细胞分泌过多的 PDGF-BB，激活周细胞中的血小板衍生生长因子受体-β（PDGFR-β）信号通路，促进新血管形成。破骨前体细胞中 PDGF-BB 的选择性敲除可减轻软骨下骨血管生成，并阻止 DMM 诱导的关节退变和软骨下神经支配。在破骨前体细胞中表达 PDGF-BB 的转基因小鼠自发重现病理性软骨下骨血管生成，并发展为关节退变和软骨下神经支配。我们的研究首次提供了证据，证明破骨前体细胞来源的 PDGF-BB 是骨关节炎发展过程中病理性软骨下骨血管生成的关键驱动因素，为开发这种疾病的早期治疗方法提供了新途径。
