Injury is a well established risk factor in the pathogenesis of osteoarthritis (OA) as supported by several large longitudinal population studies. Patients with meniscal and ACL injuries in particular are at risk for early OA. Chondroprotection of the joint surface is mediated by lubricin which forms an ordered nanofilm and provides anti-adhesion via steric repulsion. Recent observations indicate that lubricin is both downregulated and catabolized in patients with ACL injuries. This observation coupled with the rapid joint surface disruption in lubricin null mice suggest that preserving the lubricant or its restoration could play a major role in mitigating the risk of degenerative joint disease in humans with traumatic joint injuries. Resurfacing of the articular surface by re- introducing lubricin into a traumatized rat joint has been shown to slow this progress in the peri-injury period by using weekly injections of lubricin. In addition, antagonizing TNF-alpha, an inflammatory cytokine that downregulates lubricin, with etanercept has been shown to re-establish the presence of lubricin in the superficial zone of cartilage in a rat ACL model. The use of recombinant lubricin for the chondroprotection of the traumatized synovial joint could have significant commercial value. We propose 2 interconnecting specific aims engaging a well established rat ACL transection model to determine if tribosupplementation slows the progression of post-traumatic OA. In Aim 1 we will determine if the weekly addition of human lubricin reduces cartilage loss as measured by surface roughening, collagen type II degradation, GAG loss and QPCR for degradative markers. We will also determine if the co-administration of hyaluronate is more efficacious than lubricin alone. In Aim 2 we will determine if blocking the effects of TNF-alpha through the co-administration of etanercept enhances the chondroprotection achieved in Aim 1 by preventing the downstream proteolysis of the re-introduced lubricin. These aims are both translational and clinically meaningful in the management of acute joint injuries. Preliminary data indicate that tribosupplementation is achievable and is directed at the nanotribological foundation of the cartilage bearing which is characterized by very low friction. The commercial value is high as this technology would augment the widespread practice of viscosupplementation with hyaluronates. The PI is well suited for these studies as he has significantly contributed to our current knowledge of lubricin, associated cartilage friction with the appearance of wear, and is a practicing emergency physician. The PI already collaborates with the sub-contract Co-I who has established that lubricin levels are decreased in patients with ACL injuries.
Public Health Relevance: Tribosupplementing mammalian joints with lubricin can restore the protection of cartilage and prevent its damage. This practice following an injury, such as an ACL rupture, may be pivotal in protecting a joint from developing degenerative joint disease. This animal study will show that injecting lubricin into a joint can prevent joint degeneration.
Public Health Relevance Statement: Tribosupplementing mammalian joints with lubricin can restore the protection of cartilage and prevent its damage. This practice following an injury, such as an ACL rupture, may be pivotal in protecting a joint from developing degenerative joint disease. This animal study will show that injecting lubricin into a joint can prevent joint degeneration.
Project Terms: APP Secretase; Acute; Adhesions; Affect; Amyloid Precursor Protein Secretase; Animal Model; Animal Models and Related Studies; Animals; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Appearance; Arthritis; Arthritis, Degenerative; Articulation; Atrophic Arthritis; BMI percentile; BMI z-score; Binding; Binding (Molecular Function); Biocompatible Materials; Biological; Biological Function; Biological Preservation; Biological Process; Biomaterials; Body mass index; Cachectin; Cachectin-Tumor Necrosis Factor; Cartilage; Cartilage, Articular; Cartilagenous Tissue; Catabolism; Cathepsin B1; Cathepsins B; Cells; Chondrocytes; Clinical; Collagen Type II; Common Rat Strains; Contracting Opportunities; Contracts; Coupled; DIF; Data; Degenerative polyarthritis; Disease; Disorder; Down-Regulation; Down-Regulation (Physiology); Downregulation; EC 3.4.22.1; Emergencies; Emergency Situation; Enbrel; Engineering; Engineerings; Esteroproteases; Etanercept; FLR; Failure (biologic function); Fibroblasts; Film; Foreign-Body Reaction; Foundations; Friction; GAG; GAG Gene; Granulocyte Elastase; Human; Human, General; INFLM; Immune response; Immunex brand of etanercept; Incidence; Inflammation; Inflammatory; Inflammatory Arthritis; Inflammatory Response; Injection of therapeutic agent; Injections; Injury; Intellectual Property; Jobs; Joints; Knockout Mice; Knowledge; Laboratories; Lead; Left; Leukocyte Elastase; Link; Lubricants; Lubrication; Lysosomal Elastase; Mammals, Rats; Man (Taxonomy); Man, Modern; Measures; Mechanics; Mediating; Medical; Methods and Techniques; Methods, Other; Mice, Knock-out; Mice, Knockout; Modeling; Molecular Interaction; Morbidity; Morbidity - disease rate; Neutrophil Elastase; Null Mouse; Occupations; Osteoarthritis; Osteoarthrosis; PMN Elastase; Pathogenesis; Patients; Pb element; Peptidases; Peptide Hydrolases; Physicians; Play; Polymers; Polymorphonuclear Leukocyte Elastase; Population Study; Position; Positioning Attribute; Preservation, Biologic; Preservation, Biological; Process; Professional Postions; Proteases; Protein Binding; Protein Cleavage; Proteinases; Proteins; Proteolysis; Proteolytic Enzymes; Quetelet index; Rat; Rattus; Recombinants; Rheumatoid Arthritis; Risk; Risk Factors; Role; Structure of articular cartilage; Supplementation; Surface; Synovia; Synovial Fluid; TNF; TNF A; TNF Alpha; TNF gene; TNF protein, human; TNF superfamily, member 2 protein, human; TNF-2 protein, human; TNF-alpha; TNFA; TNFSF2; TNFSF2 protein, human; Techniques; Technology; Testing; Toxic effect; Toxicities; Tumor Necrosis Factor; Tumor Necrosis Factor Gene; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha (macrophage-derived); Work; Wyeth brand of etanercept; anterior cruciate ligament rupture; arthritic; articular cartilage; cost; cytokine; degenerative joint disease; disease/disorder; failure; gene product; heavy metal Pb; heavy metal lead; host response; human TNF protein; hyaluronate; hypertrophic arthritis; immunoresponse; in vivo; inhibitor; inhibitor/antagonist; injured; joint injury; lubricating glycoprotein-I; lubricin; model organism; nano; preservation; prevent; preventing; public health relevance; restoration; social role; tumor necrosis factor, human; tumor necrosis factor-2 protein, human; tumor necrosis factor-alpha promoter allele-2 protein, human
