Aged skin may drive knee osteoarthritis by sending inflammatory IL-36 signals to the joints
In mice, aging skin loses an IL-36 brake, flooding blood and joints with inflammatory signals that worsen osteoarthritis. Skin-applied microneedles blocked the effect.
Resumen
Osteoarthritis is linked to age-related low-grade inflammation, but where that inflammation comes from is unclear. Researchers found that aged skin keratinocytes lose IL-36 receptor antagonist (IL-36Ra), the brake on IL-36 inflammatory signaling. This raises IL-36 agonists in blood and joints. In mice, prematurely aged skin worsened cartilage damage, synovitis and pain after knee surgery. Removing the aged skin reduced the damage, and deleting IL-36Ra only in skin keratinocytes worsened osteoarthritis. IL-36 activated inflammatory and senescence pathways in chondrocytes and synovial fibroblasts. Blocking IL-36R signaling, including with skin-applied microneedles carrying IL-36Ra or the antibody spesolimab, reduced osteoarthritis in male mice. The findings point to skin as a possible source of systemic inflammation in joint aging, though the work is preclinical.
Resumen detallado
Osteoarthritis (OA) is common in older adults and has no approved disease-modifying drug. Low-grade, age-related inflammation is increasingly seen as a driver, but its source is unclear. Skin is the body's largest organ, and aged skin is fragile and inflammatory. Skin inflammation can also reach the joints, as in psoriatic arthritis. This study asked whether aged skin worsens OA through circulating factors.
The researchers used several mouse models of skin aging: topical D-galactose and keratinocyte-specific Zmpste24 knockout. They paired these with destabilization of the medial meniscus (DMM) surgery to induce knee OA. D-galactose-aged mice had worse cartilage loss, synovitis, bone sclerosis, osteophytes and pain, plus higher MMP13 and lower collagen II. Removing the aged skin at the time of surgery substantially reduced these changes. Injecting serum from skin-aged mice into the knees also worsened cartilage erosion. Proteomics of epidermis from young (3-month) and aged (18-month) mice flagged loss of IL-36Ra, an inhibitor of IL-36 receptor signaling made mainly by keratinocytes.
IL-36Ra fell and IL-36α/β/γ agonists rose in senescent keratinocytes, serum and joints of aged and premature-aging mice, and in UVB-aged cultured keratinocytes. Skin samples and serum from older patients with OA (about 70 years) showed the same pattern versus younger people without OA (about 35 years). In 15 OA patients, serum and synovial fluid IL-36 levels were correlated (R² about 0.32–0.47). IL-36Ra fell earlier in skin than in cartilage or synovium. Keratinocyte-specific IL-36Ra deletion raised systemic IL-36 agonists and activated NF-κB, MAPK and JAK-STAT signaling in skin, cartilage and synovium. It worsened DMM-induced OA and pain, and aggravated age-related OA by 10 months. IL-36R was found on synovial fibroblasts (not macrophages) and on chondrocytes. Medium from senescent keratinocytes induced senescence, inflammatory cytokines and catabolism in these cells. IL-36Ra or IL-36R knockdown reversed this.
Per the abstract, intra-articular inhibition of IL-36R signaling reduced OA progression. Microneedles loaded with recombinant mouse IL-36Ra or spesolimab, an anti-IL-36R antibody already approved for generalized pustular psoriasis, also attenuated OA in male mice. This suggests skin-targeted, sustained delivery as a possible disease-modifying strategy.
Caveats: the work is mainly in male mice, and the supplied text was truncated before the intervention and microneedle data, so those details rest on the abstract. Human data are small and compare young healthy people with older OA patients, so age and disease are confounded. Whether skin is the dominant source of IL-36 in humans, and whether microneedles work in people, remains untested.
Hallazgos clave
- Removing D-galactose-aged skin at the time of knee surgery reduced cartilage damage, synovitis, osteophytes and pain in mice.
- Aged and senescent keratinocytes lost IL-36Ra and raised IL-36 agonists in skin, serum and joints in mice and in older OA patients.
- Keratinocyte-specific IL-36Ra deletion worsened surgically induced and age-related OA, activating NF-κB, MAPK and JAK-STAT signaling in joint tissues.
- IL-36 signaling drove senescence, inflammation and catabolism in chondrocytes and synovial fibroblasts, reversed by IL-36Ra or IL-36R knockdown.
- Per the abstract, skin microneedles delivering IL-36Ra or spesolimab attenuated OA in male mice.
Metodología
Preclinical study combining mouse skin-aging models (topical D-galactose, keratinocyte Zmpste24 knockout, naturally aged mice) and keratinocyte IL-36Ra conditional knockout with DMM-surgery OA. Assessments included histology (OARSI), immunostaining, ELISA, RNA-seq, proteomics, von Frey pain testing and in vitro keratinocyte, chondrocyte and fibroblast cultures. Human skin, serum and synovial fluid samples were small (n=5–15 per group) and compared young non-OA with older OA patients.
Limitaciones del estudio
Experiments were mostly in male mice with surgically induced OA, so generalizability to women and to human OA is uncertain. Human data were small and confounded by age versus disease status, and the correlation between serum and synovial IL-36 does not prove skin origin. The supplied text was truncated before the intervention and microneedle experiments, so those results are summarized from the abstract only.
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