Fatty acid binding protein 4 (FABP4) as a biomarker for osteoarthritis

Abstract

Osteoarthritis (OA) is a debilitating joint disease that affects millions of individuals. However, the pathogenesis of OA is still very poorly understood. Obesity is one of the modifiable risk factors for OA, and recent studies have shown adipokines play roles in the OA pathophysiology. Fatty acid binding protein 4 (FABP4) is a novel adipokine that is closely associated with obesity and metabolic diseases. The aim of this project was to explore the potential role of FABP4 in OA. This project is consisted of three major studies. In the first study, patients with primary knee OA were included. Plasma FABP4 concentration was determined by ELISA. The correlation of plasma FABP4 and knee OA severity was investigated. In the second study, seventy-two FABP4 knockout mice (KO) in C57BL/6N background and wild-type littermates (WT) (male, 6-week-old) were fed with a high-fat diet (HFD, 60% calorie) or standard diet (STD, 11.6% calorie) for 3 months, 6 months and 9 months (n=6 each). In the parallel study, forty-eight 6-week-old male WT mice were fed with HFD or STD, and simultaneously treated with daily oral gavage of selective FABP4 inhibitor BMS309403 (15mg/kg/d) or vehicle (PBS) for 4 months and 6 months (n=6 each). Serum FABP4 and COMP concentration was quantified. Histological assessment of knee OA and micro-CT analysis of subchondral bone were performed. In the third study, in-vitro cell culture of murine chondrocyte cell line (ATDC-5) was performed. FABP4 expression of chondrocyte was examined. FABP4 was supplemented to the culture medium of ATDC-5, and catabolic factors of chondrocyte were measured by quantitative PCR and Western Blot analysis. In the first study, a total of 263 patients were included. Plasma FABP4 increased significantly with the severity of knee OA stage. In the second study, HFD induced obesity in mice. After 3 months and 6 months of HFD, KO mice showed alleviated cartilage degradation and synovitis, with significantly lower serum COMP, modified Mankin OA score, and MMP-13/ADAMTS4 expression. After 6 months and 9 months of HFD, KO mice showed less osteophyte formation and subchondral bone sclerosis. Chronic treatment of BMS309403 for 4 months and 6 months significantly alleviated cartilage degradation, but had no effects on the subchondral bone. Knocking out or pharmaceutical inhibition of FABP4 did not have significant effects on lean mice fed with STD. In the third study, chondrocyte expressed FABP4, and such expression was modulated by leptin, adiponectin, lipopolysaccharide, dexamethasone, and BMS309403. FABP4 directly induced the expression of catabolic factors of chondrocyte, including iNOS, MMP-3, and ADAMTS4. We concluded from this project that FABP4 play potential roles in the pathogenesis of OA. FABP4 may be a promising biomarker for the diagnosis and treatment of OA.