Abstract
The functional role(s) of peroxisomes in osteoarthritis remains unclear. We demonstrated that peroxisomal dysfunction in osteoarthritis is responsible for very-long-chain fatty acid (VLCFA) accumulation. Through gene-profiling analyses, we identified CRAT as the gene responsible for this event. CRAT expression was suppressed in osteoarthritis chondrocytes, and its knockdown yielded pathological osteoarthritic characteristics, including VLCFA accumulation, apoptosis, autophagic inhibition, and mitochondrial dysfunction. Subsequent miRNA profiling revealed that peroxisomal dysfunction upregulates miR-144-3p, which overlapped with the osteoarthritis pathological characteristics observed upon CRAT knockdown. Moreover, knocking down HIF-1α in normal chondrocytes suppressed CRAT expression while stimulating miR-144-3p. Our data indicate that deregulation of a HIF-1a:CRAT:miR-144-3p axis impairs peroxisomal function during the pathogenesis of osteoarthritis.
Highlights
Osteoarthritis is a degenerative joint disorder characterized by cartilage extracellular matrix degradation and cell death resulting in the gradual loss of articular cartilage integrity and damage accumulation of cartilage
Cartilage samples were obtained from osteoarthritis patients with body-mass indices (BMI) ranging from 20 - 30, and chondrocytes were isolated from the healthy and severely damaged zones to investigate this (Figure 1A)
Independent of BMI, we observed increased lipid accumulation in osteoarthritis chondrocytes compared to non-osteoarthritis chondrocytes of osteoarthritis patients
Summary
Osteoarthritis is a degenerative joint disorder characterized by cartilage extracellular matrix degradation and cell death resulting in the gradual loss of articular cartilage integrity and damage accumulation of cartilage. The significance of inter-organellar interaction has emerged recently [6, 7] and it is apparent that mitochondrial behavior is governed largely by interrelationships of the mitochondrion with other organelles, the “peroxisome-mitochondrion connection” [6,7,8]. These two organelles share metabolic pathways such as those of β-oxidation of fatty acids [9,10,11], peroxide scavenging [12], and key fissionary components such as the fission 1 (Fis1) protein, mitochondrial fission factor protein in mammals, dynamin-related protein, and Fis homologue in yeast [13,14,15,16]. We investigated the functional interconnection between mitochondria and peroxisomes in the pathogenesis of osteoarthritis
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