Osteoarthritis (OA) is a debilitating degenerative joint disease causing chronic joint pain and disability in 54 millionadults in the US. OA can result from either chronic joint use (degenerative or age-related) or from trauma (post-traumatic). At present, there is no disease modifying agent to cure or treat the disease. Clinical management focuseson weight loss, NSAIDs, corticosteroids or HA injections, and other alternative therapies aimed at reducing joints painand immobility. The final treatment, arthroplasty, is irreversible and requires revisional surgery in 10-15 years.Together, surgical and non-surgical treatments generate $27billion in healthcare costs per year. These socioeconomicburdens highlight the critical need for novel treatments to prevent or delay the cartilage damage caused by OA. Here,we propose a novel therapeutic candidate, osteoactivin (Gpnmb), a type I transmembrane glycoprotein expressed invarious cell types with anti-inflammatory and chondroprotective properties. Preliminary studies presented in thisapplication show Gpnmb is highly expressed in high-grade human osteoarthritic cartilage. When human HTB-94chondrocytes were treated with recombinant Gpnmb protein (rGpnmb) followed by IL-1b stimulation, treated cellsdemonstrated reduced expression of catabolic markers MMP-9, MMP-13, and IL-6. Furthermore, rGpnmb treatmentinhibited matrix degradation ex vivo in human cartilage explants. In vivo, intra-articular injection of rGpnmb in C57BL/6mouse joints mitigated and prevented cartilage loss in an induced post-traumatic model of OA (destabilization of themedial meniscus, DMM). We determined that Gpnmb acts via interactions in the CD44 receptor in glial cells,macrophages and chondrocytes and that CD44-null mice (CD44-/-) developed severe joint damage using the DMMmodel compared to WT littermates. Finally, we present that Gpnmb assists in slowing the progression of age-relatedmurine OA. Our lab recently identified a small Gpnmb peptide (Gpnmb-p) with the same anti-inflammatory and biologicproperties as rGpnmb. This is significant since peptides are highly selective, potent, and cheaper to produce. Peptidesalso decrease the potential for toxicity and accumulative problems than the whole protein. Therefore, in this Phase-ISBIR, we propose to evaluate efficacy and safety of rGpnmb and Gpnmb-p to mitigate and treat inflammation andarticular cartilage degradation and loss in OA. In aim one, we will assess the safety and efficacy of rGpnmb and Gpnmb-p for the treatment of induced post-traumatic osteoarthritis (PT-OA) induced via the DMM model. In aim two, we willassess the efficacy of rGpnmb and Gpnmb-p for the treatment of age-induced (degenerative) osteoarthritis in mice.For both aims, we will evaluate articular cartilage and matrix degradation using histological and imaging analyses.Successful completion of this work will demonstrate the potential therapeutic value of Gpnmb for the OA treatment withpossible extension to other applications. Public Health Relevance
Osteoarthritis (OA) is the most common form of arthritis and a major health concern affecting over 30 million in
the US, a number expected to rise substantially as the population ages. Gpnmb is a protein known to have
anti-inflammatory and chondroprotective properties. The proposed studies will test the anti-inflammatory
properties of recombinant and peptide forms of Gpnmb treatment on cartilage homeostasis in post-traumatic
(DMM) and age-related OA in vivo. A better understanding of the anti-inflammatory and chondroprotective
effects of Gpnmb will be an essential shift in the standard care for the treatment of OA and be helpful in
developing new therapeutic strategies to selectively prolong articular cartilage health and function in patients
with cartilage deterioration and loss. Adrenal Cortex Hormones ; Corticoids ; Corticosteroids ; Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Age ; ages ; Elderly ; advanced age ; elders ; geriatric ; late life ; later life ; older adult ; older person ; senior citizen ; Animals ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Non-Steroidal Anti-Inflammatory Agents ; NSAIDs ; Non Steroidal Antiinflammatory Agents ; Nonsteroidal Anti-Inflammatory Agents ; Nonsteroidal Antiinflammatory Agents ; Nonsteroidal Antiinflammatory Drug ; non-steroidal anti-inflammatory drugs ; non-steroidal antiinflammatory drugs ; nonsteroidal anti-inflammatory drugs ; Arthralgia ; Joint Pain ; Arthritis ; arthritic ; Behavior ; bone ; Cartilage ; Cartilaginous Tissue ; articular cartilage ; Cells ; Cell Body ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Eligibility Determination ; Eligibility ; Protocol Screening ; Female ; Glycoproteins ; Health ; Histology ; Homeostasis ; Autoregulation ; Physiological Homeostasis ; Human ; Modern Man ; Immunohistochemistry ; Immunohistochemistry Cell/Tissue ; Immunohistochemistry Staining Method ; Inflammation ; Intra-Articular Injections ; Intraarticular Injections ; Interleukin-6 ; B cell differentiation factor ; B cell stimulating factor 2 ; B-Cell Differentiation Factor ; B-Cell Differentiation Factor-2 ; B-Cell Stimulatory Factor-2 ; BCDF ; BSF-2 ; BSF2 ; HPGF ; Hepatocyte-Stimulating Factor ; Hybridoma Growth Factor ; IFN-beta 2 ; IFNB2 ; IL-6 ; IL6 Protein ; MGI-2 ; Myeloid Differentiation-Inducing Protein ; Plasmacytoma Growth Factor ; interferon beta 2 ; arthropathies ; Joint Diseases ; arthropathic ; arthropathy ; joint disorder ; Joints ; Knee ; Knee joint ; Life Style ; Lifestyle ; macrophage ; MÏ ; male ; Market Research ; Mus ; Mice ; Mice Mammals ; Murine ; Neuroglia ; Glia ; Glial Cells ; Kolliker's reticulum ; Neuroglial Cells ; Non-neuronal cell ; Nonneuronal cell ; nerve cement ; Ohio ; Orthopedics ; Orthopedic ; Orthopedic Surgical Profession ; Degenerative polyarthritis ; Degenerative Arthritis ; Osteoarthritis ; Osteoarthrosis ; degenerative joint disease ; hypertrophic arthritis ; osteoarthritic ; Osteogenesis ; Bone Formation ; bone tissue formation ; Patients ; Peptides ; Drug Kinetics ; Pharmacokinetics ; Proteins ; Research ; Risk ; Risk Factors ; Role ; social role ; Safety ; Mechanical Stress ; Supervision ; Miniature Swine ; Minipigs ; mini pig ; mini-swine ; miniswine ; Synovitis ; inflamed synovial tissue ; inflamed synovium ; synovial inflammation ; Testing ; Time ; Universities ; Body Weight decreased ; Weight Loss ; Weight Reduction ; body weight loss ; wt-loss ; Weight ; Work ; Bone remodeling ; bone remodelling ; Health Care Costs ; Health Costs ; Healthcare Costs ; Businesses ; chronic pain ; Gelatinase B ; 92-kDa Gelatinase ; 92-kDa Type IV Collagenase ; MMP-9 ; MMP-9 Protein ; Macrophage Gelatinase ; Matrix Metalloproteinase-9 ; Type V Collagenase ; improved ; Procedures ; Replacement Arthroplasty ; Arthroplasty ; Joint Prosthesis Implantation ; joint arthroplasty ; joint replacement ; Left ; Chronic ; Clinical ; Phase ; Biological ; Physiological ; Physiologic ; Medical ; Knockout Mice ; KO mice ; Knock-out Mice ; Null Mouse ; Physical activity ; Chondrocytes ; Cartilage Matrix ; Serum ; Blood Serum ; disability ; collagenase 3 ; MMP-13 ; MMP-13 gene product ; MMP13 gene product ; matrix metalloproteinase-13 ; Collaborations ; Intellectual Property ; Therapeutic ; Genetic Predisposition ; Genetic Susceptibility ; Inherited Predisposition ; Inherited Susceptibility ; genetic etiology ; genetic mechanism of disease ; genetic vulnerability ; genetically predisposed ; Genetic Predisposition to Disease ; Inflammatory ; Medial Menisci ; Meniscus Medialis ; Medial meniscus structure ; Disorder Management ; Disease Management ; Scientist ; joint damage ; joint trauma ; joint injury ; Clinic ; Route ; cell type ; Musculoskeletal ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; Surgeon ; Receptor Protein ; receptor ; success ; internal control ; recombinant peptide ; professor ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; Structure ; novel ; Deterioration ; Modeling ; Property ; Alternative Therapies ; osteoactivin ; preventing ; prevent ; CD44 ; MDU3 ; Pgp1 ; CD44 gene ; Data ; Ph.D. ; PhD ; Doctor of Philosophy ; randomisation ; randomization ; randomly assigned ; Randomized ; Recombinants ; in vivo ; Clinical Management ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Monitor ; C57BL/6 Mouse ; Characteristics ; socioeconomics ; socio-economic ; socio-economically ; socioeconomically ; Development ; developmental ; Pathway interactions ; pathway ; age related ; age dependent ; efficacy evaluation ; efficacy analysis ; efficacy assessment ; efficacy examination ; evaluate efficacy ; examine efficacy ; bone health ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Population ; aged ; Trauma ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; high risk ; public health relevance ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; standard care ; standard treatment ; glycoprotein NMB ; gpNMB ; cartilage degradation ; cartilage degeneration ; Bone Spur ; osteophyte ; biomarker panel ; marker panel ; histological image ; histologic image ; subchondral bone ; therapeutic candidate ; Injections ; joint inflammation ; inflamed joint ; joint swelling ;
