Aged skin exacerbates experimental osteoarthritis via enhanced IL-36R signaling

Increasing evidence suggests that age-related inflammation plays a pivotal role in osteoarthritis (OA) pathogenesis, but the mechanism is not fully understood. Here, we demonstrate that skin aging is an important driver of experimental OA progression in male mice via enhanced IL-36 receptor (IL-36R) signaling. We identified decreased IL-36 receptor antagonists (IL-36Ra) in epidermal keratinocytes from a premature-aged skin mouse model, aged mice, and patients. Decreased IL-36Ra in aged keratinocytes leads to increased secretion of IL-36 agonists to serum and joints, which activates proinflammatory signaling and promotes senescence in chondrocytes and synovial fibroblasts, thus aggravated OA progression. Genetic deletion of IL-36Ra in keratinocytes exacerbates experimental and age-related OA in male mice, whereas intra-articular inhibition of IL-36R signaling effectively attenuated OA progression. Moreover, we also generated microneedles loaded with mouse recombinant IL-36Ra protein or spesolimab, inserted them directly into skin to sustainably inhibit IL-36R signaling in epidermal keratinocytes, which both clearly attenuated OA progression in male mice. Overall, our results reveal that IL-36 agonists are age-related systemic inflammatory factors released from skin to joints and contribute to OA development. IL-36Ra shows potential clinical translational value for OA treatment, and targeting IL-36R signaling in aged skin with microneedles represents a promising disease-modifying approach.