Abstract
Much data suggests intersecting activities between the adipokine apelin (APLN) and the pathologic processes of obesity and osteoarthritis (OA), with APLN modulating cartilage, synovium, bone, and various immune cell activities. The synovium plays an important role in the pathogenesis of OA. We investigated the crosstalk between APLN, a major OA-related adipokine, and interleukin 1 beta (IL-1β), a major proinflammatory cytokine, in human OA synovial fibroblasts (OASFs). We showed that APLN stimulated the synthesis of IL-1β in a concentration- and time-dependent manner, which was mitigated by blockade of the PI3K and ERK pathway. We also showed that APLN inhibited the expression of miRNA-144-3p, which blocks IL-1β transcription; this suppression activity was reversed via blockade of the PI3K and ERK pathway. Moreover, pathologic changes in OA cartilage were rescued when APLN was silenced by shAPLN transfection both in vitro and in vivo. Our evidence is the first to show that APLN stimulates the expression of IL-1β by activating the PI3K and ERK pathway and suppressing downstream expression of miRNA-144-3p in OASFs. We also demonstrate that knockdown of APLN expression by shAPLN transfection ameliorated changes in OA cartilage severity. These results shed light on OA pathogenesis and suggest a novel treatment pathway.
Highlights
Osteoarthritis (OA) is a multifactorial disease that manifests with synovial inflammation, cartilage destruction, joint swelling and pain [1, 2]
We showed that APLN inhibited the expression of micro-ribonucleic acids (miRNAs)-144-3p, which blocks IL-1β transcription; this suppression activity was reversed via blockade of the phosphoinositide 3-kinase (PI3K) and extracellularsignal-regulated kinase (ERK) pathway
Stimulation of OA synovial fibroblasts (OASFs) with APLN did not significantly increase TNFα expression (Supplementary Figure 1). These findings indicate that APLN enhances the downstream expression of IL-1β in human OASFs, via concentration- and time-dependent manners
Summary
Osteoarthritis (OA) is a multifactorial disease that manifests with synovial inflammation, cartilage destruction, joint swelling and pain [1, 2]. Among the various risk factors, obesity has been linked to the risk of developing OA [3, 4], with the Framingham Heart Study demonstrating a 1.5- to 2-fold higher risk of www.aging-us.com developing knee OA among people who are obese compared with slimmer individuals [5]. What is known is that adipokines, multifunctional molecules secreted by adipose tissue, act as an intersecting link between obesity and OA by modulating the activities of cartilage, synovium, bone, and various immune cells [3, 7]. The synthesis of chondrolytic enzymes and proinflammatory mediators by the inflamed synovium leads to cartilage destruction, which enhances synovial inflammation, forming a vicious cycle [8, 9]. Synoviumtargeted therapy could theoretically slow OA progression and lessen the severity of OA symptoms [12, 13]
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