Pro-inflammatory cytokines are present in healthy synovium, although there seems to be a higher presence of anti-inflammatory cytokines that successfully suppress inflammation, suggesting there is an imbalance in OA [9]. In fact, levels of IL-1\(\beta\) and TNF are increased in the synovial fluid, synovium, subchondral bone, and cartilage of the OA joint [10]. The prolonged increase in these pro-inflammatory cytokines within the joint leads to an increase in expression of downstream catabolic factors, such as matrix metalloproteinases (MMPs) [11]. These MMPs are zinc-dependent enzymes that play a major role in extracellular matrix (ECM) degradation through the cleavage of type II collagen and other ECM components (e.g., aggrecan, fibronectin, and laminin) [12]. Unfortunately, cytokine-based OA treatment has not been successful, which may be due to multiple factors (i.e., drug penetration and disease stage), but most importantly could be due to the pleiotropic nature of cytokines [8; 13]. Many cytokines have overlapping actions due to shared receptors and downstream signaling pathways, making cytokine treatment difficult if targeting one individual cytokine [13]. The inflammation of the synovium, termed synovitis, is an important aspect in this perpetuation of inflammation model, as the failure to resolve this inflammation results in drastic changes to the resident cells, leading to hyperplasia, angiogenesis, and infiltrates within the synovial membrane. Infiltrating cells, such as T-cells, B-cells, plasma cells, and macrophages, then contribute to further destruction of the cartilage matrix and subchondral bone [14]. Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is crucial for natural killer cell (NK) ontogeny and CD8 T cell memory [15]. IL-15 is widely expressed by monocytes, macrophages, dendritic cells, fibroblasts, epithelial cells, and skeletal muscle [16]. There are three receptors for IL-15: (1) the specific IL-15R\(\alpha\), (2) the shared IL-2/IL-15R\(\beta\), and (3) the common IL-15R\(\gamma\), binding IL-15, -2, -4, -7, and -19. IL-15 has a high affinity for the IL-15\(\alpha\) chain but can only transduce signals in the presence of the IL-15R\(\beta\) and \(\gamma\) receptors, for which there is intermediate affinity. Important downstream signaling pathways include JAK1/STAT3, JAK3/STAT5, and NF-kB [15]. Additionally, IL-15 signaling plays a vital role in the bone turnover process. IL-15R\(\alpha\) ensures efficient osteoblast/osteoclast coupling, as well as determining osteoblast phosphate homeostasis and mineralization capacity [17]. Female \(Ill5R\alpha^{-/-}\) mice have impaired osteoclast activity and are protected from age related trabecular bone loss when ovariectomized [18]. Indeed, single nucleotide polymorphisms (SNP) of IL-15R\(\alpha\) positively correlate to total bone volume, as well as cortical bone volume [19]. Overall, IL-15 plays an important role in many body tissues and processes. Although the role of IL-15 in RA pathology has been more established, it needs to be studied separately in OA due to their differing pathological presentations [20]. IL-15 protein and mRNA levels are reported to be significantly increased in patients with OA compared to the control group [21]. Further, [PERSON] et al. (2009) found that IL-15 protein levels are higher in the synovial fluid during early OA compared to late stage, suggesting a role for IL-15 in the early stages of the disease [22]. Interestingly, another study found a positive correlation between SNPs in the human IL-15R\(\alpha\) gene and prevalence of symptomatic OA [23]. Additionally, serum IL-15 levels independently correlate to pain intensity as measured by the Western Ontario McMaster University Osteoarthritis Index (WOMAC) pain score, although they do not correlate with Kellgren-Lawrence (KL) radiographic severity [24]. The increase of IL-15 in the synovial fluid of OA patients is also positively correlated to other pro-inflammatory cytokines, as well as MMP activity [25].