Lubricin/proteoglycan 4 (encoded by the gene PRG4), a mucinous glycoprotein expressed by superficial zone chondrocytes and type B synoviocytes, is critically important in the protection and maintenance of diarthrodial joints. Lubricin provides boundary lubrication to cartilage surfaces, prevents friction-induced wear, chondrocyte apoptosis, and cartilage loss. An individual diagnosed with cruciate ligament or meniscal tears or joint inflammation can develop transient lubricin deficiency that causes irreversible loss of chondrocytes, culminating in cartilage failure years later. Pre-clinical studis by our laboratories and others show that the intraarticular injection of recombinant human PRG4 (rhPRG4) in the ACL transected or partially meniscectomized rat joint, shortly after surgery, results in more articular cartilage and signs of less degeneration than placebo-injected animals. These animals also show evidence of re-establishment of native PRG4 expression. The over expression of PRG4 in a mouse trauma model also indicated that lubricin can re- establish chondroprotection after injury. We have recently reported that rhPRG4 binds to the CD44 receptor on synoviocytes from patients with RA and blocks pro-inflammatory cytokines induced proliferation of RA synoviocytes. This effect was shown to be mediated by inhibition of nuclear factor kappa B (NF?B). We propose to study the anti-inflammatory effect of PRG4 in a model of interleukin-1 beta (IL-1) stimulated synoviocytes from patients with OA. We will investigate the modulatory effect of PRG4 on cytokine secretion by OA synoviocytes and the mechanism by which it exerts its biological effect (Aim 1).
In aim 2, we examine the biological activity of synovial fluid resident PRG4 and characterize PRG4's role across patients with different OA severities and in patients with a recent history of cruciate ligament trauma. We will also characterize the CD44-dependent effect of PRG4 in synovial fluids.
In aim 3, we will study the interaction of PRG4 and CD44 in a mouse model where PRG4 expression can be manipulated in the absence or presence of CD44. We hypothesize that the synovial hyperplasia that is observed in a PRG4 gene trap mouse that is lubricin null is dependent on CD44. Understanding these distinct modes of action will be important to many who develop transient deficiencies of lubricin following an acute joint injury or inflammatory joint disease. This is particularly true snce rhPRG4 is being developed as a device-like biologic.
Lubricin/proteoglycan-4 (PRG4) is glycoprotein that coats articular cartilage and provides lubrication in the absence of viscosity. PRG4 has a protective role in the joint. The present application focuses on a novel non- lubricating role of PRG4 and its interaction with the CD44 receptor, which is inherently anti-inflammatory. By occupying this receptor, PRG4 may decelerate the progression of inflammation in the synovium, caused by pro-inflammatory cytokines such as IL-1, which is elevated following a joint injury and in patients with osteoarthritis. This effect will in turn slow the rate of cartilage degeneration. PRG as a biologic may both lubricate cartilage surfaces and have a distinct and novel anti-inflammatory role.
