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
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 COX2
inhibitor use, relative to non-selective nonsteroidal anti-inflammatory
drug use, is associated with less progression of 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.