Osteoarthritic infrapatellar fat pad aggravates cartilage degradation via activation of p38MAPK and ERK1/2 pathways

Background: Although existing studies have suggested the involvement of the infrapatellar fat pad (IPFP) during the development of knee osteoarthritis (OA), the role of IPFP is still controversial. This study aimed to investigate the biochemical effects of osteoarthritic IPFP on cartilage and the underlying mechanisms.Methods: Human IPFP and articular cartilage were collected from end-stage OA patients during total knee arthroplasty. IPFP derived fat-conditioned medium (FCM) was used to stimulate human primary chondrocytes and cartilage explants. CCK8 was used to detect the viability of human chondrocyte. qRT-PCR and western blotting was performed to evaluate the balance of extracellular matrix (ECM) catabolism and anabolism in human chondrocytes with FCM stimulation. Functional effect of osteoarthritic IPFP was also demonstrated in human articular cartilage by ex vivo assay. Activation of relative pathways and its effects on chondrocytes were assessed through immunoblotting and inhibition experiments, respectively. Neutralization test was performed to identify the main factors and their associated pathways responsible for the effects of IPFP. Results: Osteoarthritic IPFP-derived FCM significantly induced extracellular matrix (ECM) degradation in both human primary chondrocytes and cartilage explants. Several pathways, such as NF-κB, mTORC1, p38MAPK, JNK, and ERK1/2 signaling were significantly activated in human chondrocytes with osteoarthritic IPFP-derived FCM stimulation. Interestingly, inhibition of p38MAPK and ERK1/2 signaling pathway could alleviate the detrimental effects of FCM on chondrocytes while inhibition of other signaling pathways had no similar results. In addition, IL-1β and TNF-α instead of IL-6 in osteoarthritic IPFP-derived FCM played a key role in cartilage degradation via activating p38MAPK rather than ERK1/2 signaling pathway.Conclusions: Osteoarthritic IPFP induces the degradation and inflammation of cartilage via activation of p38MAPK and ERK1/2 pathways, in which IL-1β and TNF-α act as the key factors. Our study suggests that modulating the effects of IPFP on cartilage may be a promising strategy for knee OA intervention.