Toward development of a cell-derived engineered synovial fluid for protection of cartilage matrix

Abstract

Osteoarthritis (OA) is an irreversible degenerative joint disease characterized by low-grade inflammation, mechanical inferiority, and structural changes to the various joint tissues. At the center of OA progression is the erosion of articular cartilage (AC) and its compromised interactions with the lubricating synovial fluid (SF). In healthy joints, SF-cartilage synergy make AC the smoothest natural bearing surface known to man. Inflammation-mediated destruction to the superficial cartilage and degradation to SF increase the friction coefficient at the cartilage surface. Cartilage has a limited intrinsic ability to repair itself; therefore, these phenotypic changes precede further joint degeneration. Current treatments to replenish diseased SF and restore cartilage lubrication are ineffective and at best, delay the need for joint arthroplasty.

The goal of this work is to develop a SF supplement for intra-articular delivery into OA joints. To achieve this, we stimulate fibroblast-like synoviocytes (FLS) with cytokines associated with inflammatory and tissue remodeling macrophage lineages. The research herein first shows the ability to promote long-term SF secretions in cytokine-stimulated FLS cultures as characterized by hyaluronic acid (HA) synthesis and functional changes in viscosity. We next further optimize SF lubricant and mitigate inflammatory molecule synthesis through the temporal regulation of cytokine exposure. Finally, we test the effects of our derived SF secretions on chondrocytes and show their ability to promote chondrogenic marker expression and attenuate expression of catabolic enzymes. Future work merits the characterization of these SF-like secretions for their disease-modifying ability in cartilage explants, OA chondrocytes, and animal models.