Biomarkers of knee osteoarthritis : MRI T2 mapping and fatty acid binding protein 4

Abstract

Knee osteoarthritis (OA) is a common degenerative disease that affects the whole joint. The underlying pathogenesis of OA is still unclear and no medical cure is currently available. Biomarkers are of great value in terms of improving the accuracy of diagnosis, evaluation of the efficacy of treatment, and understanding the disease’s pathomechanism.

Magnetic resonance imaging (MRI) offers a non-invasive method by which to capture qualitative changes in tissues. MRI T1ρ and T2 mapping are two promising imaging biomarkers of knee osteoarthritis. Besides these imaging biomarkers, adipokines are also emerging as biochemical biomarkers in knee OA research. FABP-4, a novel inflammatory adipokine, is an intracellular fatty acid chaperone as well as an up-stream player that regulates pivotal OA-related cytokines such IL-1, TNF-α and PPAR-ϒ. FABP-4 therefore potentially affects the homeostasis of articular cartilage. The objectives are to investigate the clinical employment of imaging biomarkers MRI T1ρ and T2 mapping in knee OA, and to study FABP-4 as a biochemical biomarker of knee OA.

1. To evaluate the clinical employment of MRI T1ρ and T2 mapping in OA, 40 patients who underwent total knee arthroplasty were recruited. The MRI T2 mapping values negatively correlated with the collagen concentrations and GAG concentrations. 2. To study the plasma levels of FABP-4 in knee OA, 244 OA patients and 90 individuals from the community were recruited. The OA patients had significantly higher levels of FABP-4 in their plasma compared to the general population. 3. To investigate the FABP-4 in the joint tissues, infrapatellar fat pad (IFP), subcutaneous adipose tissue (ScAT), synovial fluid, and plasma were harvested from OA patients who underwent total knee arthroplasty (TKA) and non-OA individuals who underwent arthroscopy surgery. The FABP-4 levels were significantly higher in the OA patients, both locally (synovial fluid) and systemically (plasma), compared with the non-OA individuals. In the OA patients, the IFP had significantly higher FABP-4 than the ScAT, although no such difference was noted in non-OA individuals. 4. To study the effects of FABP-4 on cartilage, primary chondrocytes from TKA patients were isolated and stimulated with FABP-4. FABP-4 was found to effect the expression of monocyte chemoattractant protein-1, matrix metalloproteinases-1 (MMP-1), and MMP-3 and MMP-13 in chondrocytes. 5. To address the role of FABP-4 in the pathogenesis of OA, an obesity induced OA model and an anterior cruciate ligament transection surgery induced OA model were created with FABP-4 deficient mice and their wild-type littermates. FABP-4 deficiency protected mice from obesity induced OA.

Our results suggest that MRI T2 mapping is a robust imaging biomarker for reflecting biochemical changes to the articular cartilage. MRI T2 mapping therefore shows potential to be used as a clinical instrument in early OA diagnosis and disease progress monitoring. OA patients exhibited an elevated level of FABP-4 in their plasma. The IFP from OA patients secreted abnormally high levels of FABP-4 into the synovial fluid, which could affect homeostasis in the cartilage. FABP-4 deficiency was found to protect mice from obesity induced OA. FABP-4 could be a potential therapeutic target of OA.