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

<p><span>Metabolic syndrome–associated osteoarthritis (MetS-OA)</span><span> 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. </span><span>MetS-OA mice exhibited</span><span> a rapid</span> <span>increase in joint </span><span>subchondral bone plate and trabecular thickness </span><span>before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence </span><span>at the pre- or early</span><span>-osteoarthritis stage</span><span> and </span><span>acquire a unique secretome to</span><span> stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. </span><span>At the molecular level,</span> <span>preosteoclast secretome activates </span><span>COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that </span><span>COX2 inhibitor use, relative to non-selective nonsteroidal anti-inflammatory drug use</span><span>, is associated with less</span><span> progression of </span><span>osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA. Our findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA.</span></p>