Senescent preosteoclast secretome promotes metabolic syndrome associated osteoarthritis through cyclooxygenase 2

作者：Weiping Su, Guanqiao Liu, Bahram Mohajer, Jiekang Wang, Alena Shen, Weixin Zhang, Bin Liu, Ali Guermazi, Peisong Gao, Xu Cao, Shadpour Demehri, Mei Wan · 发表于：eLife · 年份：2022 · DOI：10.7554/elife.79773 · 被引用次数：52 · 研究领域：Osteoarthritis Treatment and Mechanisms、Bone Metabolism and Diseases、Oral microbiology and periodontitis research

Background: Metabolic syndrome–associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA. Methods: Analysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system. Results: Humans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At ...