HIF-1α:CRAT:miR-144-3p axis dysregulation promotes osteoarthritis chondrocyte apoptosis and VLCFA accumulation

Jinsoo Song; Yeon-Ho Kang; Sik Yoon; Churl-Hong Chun; Eun-Jung Jin

doi:10.18632/oncotarget.20615

HIF-1α:CRAT:miR-144-3p axis dysregulation promotes osteoarthritis chondrocyte apoptosis and VLCFA accumulation

Oncotarget. 2017 Sep 1;8(41):69351-69361. doi: 10.18632/oncotarget.20615. eCollection 2017 Sep 19.

Authors

Jinsoo Song¹, Yeon-Ho Kang¹, Sik Yoon², Churl-Hong Chun³, Eun-Jung Jin¹

Affiliations

¹ Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, Korea.
² Department of Anatomy, Pusan National University School of Medicine, Yangsan, Korea.
³ Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Chunbuk, Korea.

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.

Keywords: CRAT; Gerotarget; HIF-1α; miR-144-3p; osteoarthritis; very-long-chain fatty acid.