Abstract

This study aimed to investigate the biochemical effects of osteoarthritic infrapatellar fat pad (IPFP) on cartilage and the underlying mechanisms. Human IPFP and articular cartilage were collected from end-stage osteoarthritis (OA) patients during total knee arthroplasty. IPFP-derived fat-conditioned medium (FCM) was used to stimulate human primary chondrocytes and cartilage explants. Functional effect of osteoarthritic IPFP was explored in human primary chondrocytes and articular cartilage in vitro and ex vivo. 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. 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 key roles in cartilage degradation via activating p38MAPK rather than ERK1/2 signaling pathway. 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.

Highlights

  • Osteoarthritis (OA) is the most frequent joint disorder, characterized by structural alterations involving the whole joint

  • Our study suggests that modulating the effects of infrapatellar fat pad (IPFP) on cartilage may be a promising strategy for knee OA intervention

  • Little effect of IPFP-derived fat-conditioned medium (FCM) on cell viability was observed by Cell counting kit-8 (CCK8) assay (Supplementary Figure S1). quantitative real-time polymerase chain reaction (qRT-PCR) indicated that FCM upregulated the expression of extracellular matrix (ECM) catabolic markers including MMP1, MMP3, and ADAMTS4 in a dose-dependent manner (Fig. 1B)

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Summary

Introduction

Osteoarthritis (OA) is the most frequent joint disorder, characterized by structural alterations involving the whole joint. The pathogenesis of OA includes cartilage degradation, subchondral bone remodeling, osteophyte formation and synovial inflammation, which leads to joint pain, tenderness, swelling, stiffness and limitation of movement [1, 2]. It has caused a huge socioeconomic burden worldwide due to its disabling characteristics and an unmet medical need [3, 4]. 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

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