Interfering with transforming growth factor-β (TGFβ) signalling by targeting IL-36 family cytokines could have disease-modifying effects in osteoarthritis (OA), according to new research in mouse models of OA and in tissue from patients with the disease. Li et al. suggest that IL-36 receptor antagonist (IL-36RN in humans; IL-36Ra in mice) might be a future therapy for OA.

Credit: Springer Nature Limited

Previous studies have implicated altered TGFβ signalling in the development and progression of OA, but global inhibition of TGFβ activity could have negative multi-organ effects, suggesting the need for alternative approaches. The present study demonstrates the feasibility of attenuating OA by targeting a TGFβ type 2 receptor (TGFBR2)–IL-36 signalling axis relevant to joint development and homeostasis.

Li et al. demonstrated that Tgfbr2–/– mice spontaneously developed OA and also had more severe post-traumatic OA (induced by destabilization of the medial meniscus (DMM)) than control mice. Genetic ablation of Tgfbr2 was accompanied by increased expression of IL-36α and IL-36 receptor (IL-36R) and decreased expression of IL-36Ra; similar expression patterns of these cytokines and receptors were observed in wild-type mice treated with a TGFβ inhibitor (SB-505124), in ageing mice with naturally occurring OA and in wild-type mice with DMM-induced post-traumatic OA.

Consistent with these findings, blocking TGFBR2 signalling in primary cultures of human articular chondrocytes with SB-505124 led to dose-dependent increases in IL-36α, IL-36R and matrix metalloproteinase 13 (MMP13) and a decrease in IL-36RN. Furthermore, examination of articular cartilage tissue from human donors (with or without OA-like degenerative changes) revealed a pattern of gradually decreasing TGFBR2 expression and gradually increasing IL-36α, IL-36R and MMP13 expression that correlated with increasing severity of cartilage degeneration.

Demonstrating the therapeutic potential of targeting the TGFBR2–IL-36 axis, intra-articular injection of IL-36Ra attenuated OA progression in Tgfbr2–/– mice as well as in wild-type mice with DMM-induced OA; by contrast, injection of IL-36α exacerbated OA in both models. In human articular chondrocytes from donors with end-stage OA, treatment with IL-36RN led to a dose-dependent decrease in MMP13 expression in vitro.

IL-36 receptor antagonist…might be a future therapy for OA

Together, the results of the study suggest that targeting IL-36 signalling could attenuate the OA process.