Targeting IL-22 and IL-22R protects against experimental osteoarthritis

Osteoarthritis (OA) is characterized by cartilage degradation, pain, and synovitis.¹ Joint inflammation driven by cytokines has been demonstrated to cause cartilage degradation and pain.² However, approaches to neutralize cytokines, such as IL-1 and TNF-α, known to be involved in OA have shown poor clinical efficacy.³ There is an unmet clinical need to find better anti-inflammatory and pain targets for OA therapy and to elucidate the role of other cytokines in OA pathogenesis. Previous studies have shown that IL-22 and its receptor IL-22R play central roles in inflammation and diseases such as psoriasis, ulcerative colitis, graft-versus-host disease, certain infections and tumors, as well as in liver and pancreas damage.^4,5 The role of IL-22/IL-22R and the potential for therapeutic targeting of both proteins in OA remain largely unknown, which we sought to investigate.

We first examined human OA tissues to investigate whether IL-22/IL-22R expression levels change in disease. IL-22 was increased in the synovial fluid (SF) but not in the sera of OA patients compared to non-OA patients (Fig. 1a, b). Protein and mRNA expression of IL-22R was elevated in human chondrocytes isolated from OA patients (Fig. 1c–e). However, IL-22 protein and mRNA expression was only increased in fibroblast-like synoviocytes (FLS) isolated from OA patients (Fig. 1f–h). The increased concentration of IL-22 in the SF but not in the sera of OA patients seems to suggest that this cytokine plays a local role in OA joints with tissue-specific expression. It seems plausible that IL-22 produced by FLS in OA joints is important for disease progression. FLS-produced IL-22 may act mainly on IL-22R on chondrocytes, as indicated by the elevated expression levels of the receptor in human OA chondrocytes. Although IL-22/IL-22R have been reported to be increased in inflamed OA synovium and linked with increased protease expression,^6,7 further studies investigating the precise downstream signaling of IL-22/IL-22R in chondrocytes need to be conducted.

Fig. 1.

Targeting IL-22 signaling protects against experimental osteoarthritis. IL-22 concentration (pg/mL) in a SF and b serum of non-OA and OA patients (n = 25). c IL-22 mRNA, d IL-22R mRNA and e IL-22 and IL-22R protein expression in isolated human chondrocytes from non-OA and OA patients (n = 18). f IL-22 mRNA, g IL-22R mRNA and h IL-22 and IL-22R protein expression in isolated FLS from non-OA and OA patients (n = 18). i, j OARSI scoring of cartilage and k von Frey pain assessment of sham- or DMM-operated IL-22R^fl/fl control mice and IL-22R^{Acan Cre-ERT2} mice (12 weeks post surgery end timepoint) (n = 20). l, m OARSI scoring of cartilage and n von Frey pain assessment from sham- or DMM-operated WT mice treated i.a. with either IgG1 (control; 50 µg per mouse; 3 times per week for 12 weeks post surgery) or αIL-22R (50 µg per mouse; 3 times per week for 12 weeks post surgery) (n = 20). All RT-qPCR gene expression levels were normalized to the endogenous level of 18S in the respective groups. Data are expressed as the mean ± SEM with two-tailed t-test or two-way analysis of variance followed by the Tukey-Kramer test or repeated measures 2-way ANOVA with Bonferroni’s post hoc tests. n indicates the number of human specimens or mice per group. NS nonsignificant. ***p < 0.001 or ****p < 0.0001 is represented in all figures

Having observed the tissue-specific increase in IL-22 in chondrocytes and IL-22R in FLS from OA patients, we next investigated whether these results had an in vivo relevance during disease pathogenesis. We tested this hypothesis first by successfully generating inducible IL-22R chondrocyte-specific KO mice (IL-22R^{Acan Cre-ERT2}) (Supplementary Fig. S1a, b). IL-22R^{Acan Cre-ERT2} mice displayed decreased cartilage degradation, synovitis, osteophyte maturity and pain compared to IL-22R^fl/fl control mice post experimental OA (surgical destabilization of the medial meniscus (DMM)) (Fig. 1i–k and Supplementary Fig. S1c–e). We also successfully generated inducible IL-22 FLS-specific KO mice (IL-22^{Col1a2 Cre-ERT2}) (Supplementary Fig. S2a, b). IL-22^{Col1a2 Cre-ERT2} mice demonstrated reduced disease outcomes and pain compared to IL-22^fl/fl control mice post DMM surgery (Supplementary Fig. S2c–h). To our knowledge, this is the first set of in vivo data that show, using tissue-specific KO mice, the pathogenic role of IL-22/IL-22R in both OA disease progression and OA-related pain. IL-22 in RA joints has both beneficial⁸ and pathogenic⁹ roles; together with our results, this may suggest that IL-22 is part of divergent inflammatory responses orchestrated by different joint cells in OA compared to RA.

Next, we wanted to investigate whether therapeutically neutralizing IL-22 and IL-22R may attenuate OA in vivo. WT mice treated with an IL-22R neutralizing antibody demonstrated decreased cartilage degradation, synovitis, osteophyte maturity and pain compared to IgG1-treated control mice post DMM surgery (Fig. 1l, m and Supplementary Fig. S3a–c). Similarly, WT mice treated with an anti-IL-22 antibody displayed reduced disease outcomes (Supplementary Fig. S4a–f). Our in vivo studies also showed the possible potential of using anti-IL-22/IL-22R antibodies to treat OA and its related pain. A number of basic studies and clinical trials have shown the benefits of targeting IL-22/IL-22R in systemic immune diseases.⁴ Our study indicates a further benefit of administering anti-IL-22/IL-22R in the joint to avoid any adverse systemic effects.¹⁰

Together, our data reveal the cell-specific pathogenic role of IL-22 (FLS specific) and IL-22R (chondrocyte specific) in OA. Targeting both IL-22 and IL-22R seems to be a plausible treatment option for OA and pain.

Author contributions

Design and experimentation: C.Y., J.L., and P.K.S.; supervision: Y.Y., Q.J., and P.K.S.; and manuscript writing: P.K.S.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version of this article (10.1038/s41423-020-0491-y) contains supplementary material.