Background/Purpose: IL-23 mediated inflammatory diseases such as psoriasis and psoriatic arthritis are associated with bone loss in addition to more classical features such as skin and joint inflammation. Inflammation-induced bone loss has long been assumed to be directly due to inflammatory cytokines, such as TNF or IL-17. Here, we provide evidence that inflammation-induced bone loss is mediated via the stress-induced cytokine, Growth Differentiation Factor 15 (GDF15). GDF15 is a well-known mediator of weight loss through aversion to food. It acts exclusively through a single receptor found in the hindbrain, GFRAL (glial cell line-derived neurotrophic factor (GDNF) family receptor α-like), which triggers systemic effects through activation of the sympathetic nervous system (Suriben et al. 2020. Nat Med).

Methods: GDF15 levels in SpA patients, selected by ASAS criteria, were determined using ELISA (R&D cat. DY957). Stable overexpression of GDF15 or IL-23 in mice was performed by using in-house designed EEV (Enhanced Episomal Vectors). GFRAL deficient mice were generated by CRISPR/Cas9 editing to evaluate the GFRAL dependency of GDF15 mediated effects. Systemic and joint Inflammation in mice was quantified clinically, and by histopathology, flow cytometry and RNA sequencing. Quantitative bone analysis was performed by µCT using an in-house developed script in FiJi software (FiJi is Just ImageJ).

Results: We found serum GDF15 to be elevated in spondyloarthritis patients, especially those with co-morbid psoriasis. We used GDF15-EEV to induce sustained, systemic overexpression of GDF15. GDF15 overexpression did not result in skin, gut or joint inflammation. As expected, GDF15 overexpression caused weight loss, however revealed dose-dependent GDF15-induced trabecular bone loss (Figure 1). Gene expression showed a marked upregulation in osteoclast genes. Intriguingly, caloric restriction alone was not able to replicate GDF15-induced trabecular bone loss, suggesting the existence of a GDF15 mediated brain-bone axis.

IL-23 overexpression by EEV causes psoriatic-like inflammation in mice, coupled with bone and weight loss. We found serum GDF15 to be increased in mice with elevated IL-23 (control: 45.51 +/- 2.774 ; IL-23: 91 +/- 11.71 pg/ml, p < 0.01), indicating IL-23 mediated induction of GDF15. To evaluate whether the IL-23 mediated bone loss was mediated by GDF15 we induced IL-23 overexpression in the absence of GDF15 or GFRAL. Curiously, both GDF15-KO and GFRAL-KO mice showed significant protection against IL-23 induced weight and bone loss but displayed no protection against skin inflammation (Figure 2: * p < 0,05, ** p < 0, 01).

Conclusion: GDF15 was found to be a novel regulator of bone homeostasis. IL-23 driven inflammation induces GDF15, which in turn mediates trabecular bone loss, but does not participate in inflammation severity. Collectively, these data suggest the existence of a brain-bone axis driving the IL-23 mediated bone loss in psoriasis and psoriatic arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-23-induced-growth-differentiation-factor-15-contributes-to-trabecular-bone-loss-but-does-not-affect-skin-gut-or-joint-inflammation-in-psoriatic-arthritis/