Background/Purpose: Aberrant infrapatellar fat metabolism is a prominent feature that exacerbates inflammation and fibrosis relative to joint deterioration during osteoarthritis (OA). Irisin, a secretory subunit of fibronectin type III domain containing 5 (FNDC5), is found to regulate adipose morphogenesis, energy expenditure, skeletal muscle, and bone metabolism. This study is undertaken to investigate the association of Irisin expression and end-stage knee OA and verify whether Irisin signaling changed infrapatellar fat remodeling and joint homeostasis in the progression of OA.

Methods: Injured articular specimens were harvested from 19 patients with end-stage knee OA and 11 patients with femoral neck fracture (non-OA) who required total hip arthroplasty. Knee joints in mice that overexpressed FNDC5 were subjected to suprapatellar injection of collagenase to provoke OA. Expressions of Irisin, adipokines, and MMPs were probed with RT-quantitative PCR. Infrapatellar adiposity, cartilage damage, and synovial integrity were verified with histomorphometry and immunohistochemistry. Irisin recombinant protein was produced for the treatment of collagenase-affected knees.

Results: Infrapatellar adipose and synovial tissues instead of articular cartilage exhibited distinguishable Irisin immunostaining. Injured specimens from the end-stage OA group showed 40% decline in Irisin expression compared with those in the non-OA group. In vitro, a gain of Irisin function enabled synovial fibroblasts but not chondrocytes to display minor responses to the IL-1β provocation of MMP3 and MMP9 expression. Of note, Irisin signaling enhancement resulted in 85% decrease in adipogenic gene expression and 65% reduction in adipocyte formation of mesenchymal progenitor cells. In collagenase-mediated knee OA pathogenesis, the FNDC5-overexpressing mice showed moderate responses to infrapatellar adipose hypertrophy concomitant with slight synovial hypercellularity and membrane hyperplasia within the affected joints. These adipose-regulatory actions warded off the affected knees from cartilage destruction and gait aberrance. Likewise, administration of Irisin recombinant protein mitigated the development of infrapatellar adiposity and synovitis, a remedial effect that slowed down the progression of articular cartilage erosion and walking profile irregularity. Affected joints and adipocytes responded to the Irisin recombinant protein treatment by reducing the expressions of cartilage-deleterious adipokines IL-6, leptin, and adiponectin through regulating PPARγ function.

Conclusion: Irisin dysfunction is relevant to the occurrence of end-stage knee OA. Irisin signaling protects from excessive adipogenesis of mesenchymal precursor cells and diminishes inflammation and cartilage catabolism actions aggravated by adipocytes and synovial cells. This study sheds an emerging new light on the Irisin signaling stabilization of infrapatellar adipose homeostasis and the prospective of the therapeutic potential of Irisin recombinant protein for deescalating knee OA development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/irisin-ameliorates-infrapatellar-adiposity-in-knee-osteoarthritis-pathogenesis-by-orchestrating-adipokine-signaling/