The Age-dependent Influence of the Infrapatellar Fat Pad on Chondrocyte Extracellular Matrix Production

Abstract

Despite the growing burden of knee osteoarthritis on aging populations, our mechanistic understanding of this disease remains lacking. Though knee osteoarthritis is a whole joint disease, the impact of intra-articular structures such as the infrapatellar fat pad (IFP) on cartilage health is unclear. This study investigated the effect of age on paracrine communication between the IFP and chondrocytes. To isolate the effects of the IFP secretome on chondrocytes, aged chondrocytes from male and female mice were incubated with conditioned media from sex-matched young IFPs, aged IFPs, or control media. Extracellular matrix protein expression increased in both male and female chondrocytes exposed to young, but not aged, conditioned media relative to control media. The effect of the young IFP was not concomitant with changes in extracellular matrix degradation proteins, ADAMTS4 or MMP13. To identify factors mediating the effects of the IFP on chondrocytes that are altered with aging, we performed mass spectrometry of young and aged conditioned media and transcriptomics of aged chondrocytes treated with young or aged conditioned media. We then integrated the 2 datasets using network analyses. From the conditioned media, 2 secreted proteins, Mfge8 and Apoa4, were significantly changed with aging. In silico perturbation of the corresponding receptors of these IFP-secreted factors identified multiple enriched pathways in chondrocytes, including negative regulation of nitric oxide synthase activity. Overall, the data suggest that young IFPs release paracrine factors that promote extracellular matrix production in chondrocytes, potentially via regulation of nitric oxide levels, but that this effect is diminished with aging.

Keywords: Adipose; Knee osteoarthritis; Multiomics; Nitric oxide signaling; Paracrine signaling.