Senescent preosteoclast secretome promotes metabolic syndrome-associated osteoarthritis through COX2-PGE2

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. Here, we report that 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 the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitor...代谢综合征相关骨关节炎（Metabolic syndrome–associated osteoarthritis, MetS-OA）是一类以同时存在代谢综合征（Metabolic syndrome, MetS）或其任一独立组分作为定义特征的独特骨关节炎表型。尽管MetS-OA的患病率居高不下，但其致病机制仍未阐明。本研究发现，相较于未罹患代谢综合征的个体，罹患代谢综合征的人类与小鼠更易出现骨关节炎相关的软骨下骨病变。MetS-OA模型小鼠在关节软骨发生退变之前，其关节软骨下骨板与骨小梁厚度即出现快速增厚。在骨关节炎前期或早期阶段，软骨下前破骨细胞会发生细胞衰老，并获得独特的分泌组谱，以刺激成骨细胞分化同时抑制破骨细胞分化。拮抗前破骨细胞衰老可显著缓解MetS-OA模型小鼠的病理性软骨下骨改变与骨关节炎进展。在分子层面，前破骨细胞的分泌组可激活环氧合酶2-前列腺素E2（COX2-PGE2）通路，进而促进成骨祖细胞的分化……