The Role of Interleukin-6 Signaling in Osteoarthritis Associated Cartilage Degradation and Pain

Osteoarthritis (OA) and post-traumatic OA (PTOA) are prevalent joint disorders and leading causes of chronic pain. While pain is a primary symptom of OA and the reason individuals seek medical attention, the pathology of OA also includes physical manifestations such as articular cartilage and meniscus degeneration, synovial hyperplasia, osteophyte formation, and subchondral bone sclerosis. Despite the extensive socioeconomic burden of OA, effective treatments for both OA-associated joint degeneration and pain are not yet available due to our poor understanding of the mechanisms underlying the disease. The physical manifestations of OA are caused by imbalanced catabolic and anabolic responses and pro-inflammatory changes; however, their connection to pain is not well studied. Because Interleukin-6 (IL-6) is involved in cartilage degradation and conditions of inflammatory pain, we examined whether IL-6 signaling is a driver of both PTOA-associated cartilage degradation and pain. Our data demonstrate that genetic removal of Il6 attenuates PTOA-associated cartilage catabolism, decreases innervation of the knee joint, and reduces nociceptive pain signaling, without improving PTOA-associated subchondral bone sclerosis or chondrocyte apoptosis in male and not female mice. Compared to wild-type controls, the activation of IL-6 downstream mediators, STAT3 and ERK, were reduced in both knees and dorsal root ganglia of Il6-/- male mice following knee injury, while female mice showed a different signaling pattern. Using specific pharmacological inhibitors of STAT and ERK signaling in cartilage and DRG explants, we demonstrated that Janus kinases (JAKs) were critical regulators of STAT and ERK signaling in both cartilage catabolism and pain. STAT3 promoted cartilage catabolism downstream of JAK, but inhibition of STAT3 decreased cartilage anabolism and enhanced pain signals. JAK-dependent ERK activation was important for neurite outgrowth and pain signaling; however, ERK inhibition was less effective than JAK inhibition in reducing cartilage catabolism. Based on the essential role of IL-6 in regulating both cartilage degradation and pain in PTOA, and due to the upregulation of IL-6 in NOTCH-induced OA demonstrated by our lab previously, we examined the necessity of IL-6 at downstream of NOTCH signaling in cartilage degeneration and pain. We generated an alternative less severe NOTCH GOF OA model (AcanCreERT2; R26-NICDf/+), and demonstrated that cartilage-specific removal of Il6 (AcanCreERT2; R26-NICDf/+; Il6f/f) is not sufficient to reduce NOTCH induced joint cartilage degeneration and pain. Collectively, these data demonstrated that IL-6 mediates both cartilage degradation and pain associated with PTOA in a sex-specific manner and provides critical details regarding the tissue-specific contributions of downstream effectors of IL-6 signaling, which are potential therapeutic targets for disease-modifying osteoarthritis drugs.