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.
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.
References
Original article
Li, T. et al. TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Sci. Transl. Med. 11, eaan2585 (2019)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Onuora, S. IL-36 inhibition to treat OA. Nat Rev Rheumatol 15, 386 (2019). https://doi.org/10.1038/s41584-019-0250-6
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41584-019-0250-6