Novel adipokine associated with OA: retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients

Abstract

Objective Retinol binding protein 4 (RBP4) is a member of the lipocalin family and a vitamin A carrier in the blood. More recently, RBP4 has been described as an adipokine that is involved in insulin resistance and metabolic syndrome (MetS). As obesity, MetS and some adipokines contribute to the pathogenesis of osteoarthritis (OA), we investigated RBP4 in patients with OA. Materials and methods Cartilage, synovial fluid and blood samples were collected from 100 OA patients undergoing total knee replacement surgery. Primary chondrocytes and cartilage tissue were cultured to measure the RBP4 expression. The concentrations of RBP4, other adipokines (adipsin, adiponectin, leptin and resistin) and biomarkers of OA (COMP, MMP-1, MMP-3 and YKL-40) were measured by immunoassay, and gene expression was measured by next-generation RNA sequencing. Results The OA cartilage samples released RBP4 into the culture medium, and the levels correlated positively with the expression of the adipokines adipsin, adiponectin, leptin and resistin. RBP4 was the most prominently expressed of these adipokines in the OA chondrocytes, and the expression of the RBP4 receptors STRA6 (stimulated by retinoic acid gene homologue 6) and TLR4 (Toll-like receptor 4) was also detected. Within the cartilage culture medium, RBP4 showed a positive correlation with MMP-1, MMP-3 and YKL-40. RBP4 was also present in the synovial fluid from the OA patients and correlated positively with the concentrations of RBP4 found in the plasma and the cartilage culture medium. Plasma RBP4 concentrations also showed a positive correlation with MMP-3 and adipsin. Conclusions We show here, for the first time, that RBP4 is produced within OA joints and that it is associated with increased levels of adipokines and MMPs. The results suggest a role for RBP4 in the pathogenesis of OA and as a possible target for the disease-modifying drugs for the treatment of OA.

Allelic expression imbalance in articular cartilage and subchondral bone refined genome-wide association signals in osteoarthritis

“…In the other hand, we found seven drugs which has been already approved to be used, including Retinol which interacts with ALDH1A2 gene and Ivabradine which interacts with the lncRNA MALAT1. The Retinol binding protein 4 (RBP4) acts as an immunomodulatory adipocytokine (a bioactive product produced by adipose tissue), and recently was found positively correlated with MMP-1 and MMP-3 in chondrocytes and highly expressed in synovial fluid and plasma from OA patients (27), suggesting a possible role of this molecule in the OA pathogenesis. Moreover, Ivabradine was found to induce up-regulation of matrix metalloproteinase-3 (MMP-3) and MMP-13 at gene and protein levels (28), which are key genes for OA pathophysiology.…”

Adipokine role in physiopathology of inflammatory and degenerative musculoskeletal diseases

“… 142 The serum and synovial level of RBP-4 was recently assessed for the first time in a series of patients with osteoarthritis, resulting in a high level of the cytokine either in synovial fluid or in serum, and a correlation with the level of MMP-1 was pointed out. 143 However, in a study that included 101 patients with rheumatoid arthritis, retinol-binding protein 4 serum levels did not correlate with the presence of insulin resistance and β-cell function. Therefore, the mechanisms leading to insulin resistance in patients with this chronic inflammatory disease may be different from those occurring in obesity or diabetes.…”

Interplay of retinol binding protein 4 with obesity and associated chronic alterations (Review)

“…RBP4 levels are significantly elevated in patients with psoriatic arthritis and psoriasis ( 80 ). In addition, RBP4 is secreted in osteoarthritic joints and is positively associated with expression levels of other adipokines and extracellular matrix metalloproteinases (MMPs) 1 and 3 ( 82 ). However, a Mendelian randomization study found no association between RBP4 levels and osteoarthritis ( 83 ).…”