Joint injury is a well established risk factor in the pathogenesis of post-traumatic osteoarthritis (PTOA). In particular, patients with meniscal tears are at high risk for early PTOA. Chondroprotection of the joint surface is mediated by lubricin, a large glycoprotien which forms a lubricating nanofilm on the cartilage surface and provides anti-adhesion via steric repulsion. Recent observations indicate that lubricin is both downregulated and catabolized in patients following traumatic joint injuries. This observation, coupled with the rapid joint surface disruption in lubricin null mice, suggest that preserving or restoring the lubricant could play a major role in mitigating the risk of degenerative joint disease in patients with meniscal injuries, either before or after partial meniscectomy. Our Phase 1 studies clearly show that re-introducing lubricin into the anterior cruciate ligament injured rat joint ("tribosupplementation") slowed PTOA pathogenesis in the peri-injury period following either weekly intra-articular injections or a single dose, escalated injection of recombinant human lubricin. The use of recombinant lubricin for the chondroprotection of the traumatized synovial joint thus could have significant commercial value as a new therapeutic treatment. In Phase II, we propose three interconnecting specific aims based on our well established pre-clinical model of joint injury to determine if tribosupplementation slows the progression of PTOA following partial meniscectomy.
In Aim 1, we will determine if the co-administration with hyaluronate is more efficacious than recombinant human lubricin alone in enhancing the chondroprotection in a porcine cartilage bearing.
In Aim 2, we will determine if this potentiating effect results in a greater reduction in chondrocyte apoptosis, especially in the presence of cartilage which has been degraded by IL-1.
In Aim 3, we will determine if recombinant human lubricin reduces cartilage loss following partial medial meniscectomy, in vivo, as measured by histology, collagen type II degradation, GAG loss and qPCR for degradative markers.
These aims are translational and will provide the foundation for a clinical trial. Our preliminary data indicate that tribosupplementation is achievable and is directed at the nanotribological foundation of the cartilage bearing, which is characterized by very low cartilage friction. The commercial value is high as this technology could improve the widespread practice of viscosupplementation with hyaluronate. The PI and his research team are well suited to perform these studies in that they have significantly contributed to the current knowledge of lubricin and its association with cartilage friction, cartilage wear, and chondrocyte apoptosis. The PI is also a practicing emergency physician and already collaborates with the sub-contract Co-I, who has also performed several large animal studies to date.
Tribosupplementing mammalian joints with recombinant human lubricin can restore the protection of cartilage and prevent its damage. This practice following an injury, such as a meniscal tear or operative partial meniscectomy, may be pivotal in protecting a joint from developing degenerative joint disease. This animal study will show that injecting pre-commercialized lubricin protein into a joint can prevent joint degeneration.
|Jay, Gregory D; Waller, Kimberly A (2014) The biology of lubricin: near frictionless joint motion. Matrix Biol 39:17-24|