Background/Purpose:

Obesity is a major risk factor for the development of osteoarthritis (OA). Altered biomechanics have been postulated as the main causative mechanism, but recent data showing a higher incidence of hand OA in obese patients suggest the existence of a systemic component. Obesity is commonly associated with a state of low-grade inflammation, increased circulating adipokines and free fatty acids (FFA) released by adipose tissue. Whereas low-grade inflammation has received some attention in the recent years, little is known about the role of FFAs in OA pathogenesis. The aim of this study was to analyze effects of saturated (palmitate) and monounsaturated (oleate) FFAs on articular cartilage and chondrocytes.

Methods:

Human Articular Chondrocytes (hAC) obtained from young healthy donors (21.3±2.9 years) were grown in monolayer cultures until confluence. For cell viability and caspase 3/7 activation assays, hAC were treated with 0.5 mM palmitate, 0.5 mM oleate or vehicle, in the presence or absence of 1 ng/ml IL-1β for 72 hours. For gene expression studies, shorter treatment time (24-hours) and lower IL-1β concentration (10 pg/ml) were used. Levels of proinflammatory factors, extracellular matrix proteins, extracellular proteases and endoplasmic reticulum (ER) stress markers were measured. In addition, bovine articular cartilage explants were cultured with FFA for 72 with or without IL-1β and cartilage integrity was studied.

Results:

Palmitate induced caspase 3/7 activation and cell death in IL-1β -stimulated hAC, and significantly upregulated IL-1β -induced IL-6 and Cox-2 gene expression as well as IL-6 protein secretion, whereas oleate had no additive effect. Exposure to FFAs did not modify type II collagen, aggrecan, ADAMTS-4, -5, and MMP13 gene expression after 24 hours. ER stress markers were potently increased by palmitate alone, but not oleate, and this effect was further enhanced by IL-1β. Preliminary experiments showed that palmitate accelerated cartilage destruction driven by IL-1β in bovine explants, as evidenced by a significant increase in cell death and glycosaminoglycan release.

Conclusion:

Saturated fatty acids, specifically palmitate, have catabolic effects on articular cartilage and can accelerate its breakdown in the context of low-grade inflammation by synergizing with IL-1β  to increase proinflammatory mediators, ER stress and caspase-associated cell death. Collectively, our data suggest that elevated levels of saturated FFA may contribute to OA pathogenesis in obese patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/saturated-fatty-acids-act-synergistically-with-interleukin-1-beta-to-increase-inflammation-endoplasmic-reticulum-stress-and-cell-death-in-human-articular-chondrocytes/