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Principal Investigator: Moses O Oyewumi
Organization: NORTHEAST OHIO MEDICAL UNIVERSITY
Fiscal Year: 2024
Award: $406,394
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Summary
The use of autogenous bone graft is the most common clinical approach for bone regeneration. Although, the
practice has resulted in high rates of fusion success, there are challenges with increased operative time, limited
availability of autologous bone, blood loss and donor-site morbidity. Thus, there is a significant attention on
therapeutic agents that can promote bone regeneration, as suitable alternatives to autogenous grafts.
Meanwhile, the effectiveness of many of the current osteogenic therapeutic approaches is plagued by safety
concerns. We propose an innovative treatment strategy for bone regeneration that is based on Gpnmb,
discovered by our group. We identified Gpnmb (osteoactivin, OA) as a novel bone anabolic agent that also acts
as a positive regulator of osteoblast (OB)-mediated bone formation. The Gpnmb cDNA encodes transmembrane
proteins (~574 amino acids) that are heavily glycosylated with several functional domains. We found that the
recombinant Gpnmb protein (rGpnmb, containing 472 amino acids) derived from the extracellular portion of
Gpnmb possesses remarkable osteoinductive and osteogenic properties. A new peptide (Gpnmb-p containing
18 amino acids; 2kDa) derived from the intracellular portion of Gpnmb showed comparable efficacy with rGpnmb.
We observed that without a suitable delivery system, upon injection, Gpnmb-p diffuses way from injection site.
The thermoresponsive hydrogel platform will ensure that Gpnmb-therapeutics can reach fusion site (in liquid
form) while maintaining the effective dose at bone regenerative site through sol-gel transition that occurs at
physiological temperature. The overarching hypothesis of our project is that delivery of Gpnmb-therapeutics
using thermoresponsive hydrogels at the bone fusion site will promote osteogenic differentiation and
function as well as angiogenic response while minimizing off-target distribution leading to improved
efficacy and safety. The project will proceed via three specific aims: (1) To fabricate and characterize
thermoresponsive Gpnmb-hydrogels. In this aim, we will prepare and characterize thermoresponsive Gpnmb-
hydrogels using triblock PLA-b-PEG-b-PLA copolymer platform. (2) To assess the mechanistic basis by which
Gpnmb-hydrogels promote OB differentiation/function and angiogenesis. We expect to reveal and compare key
molecular targets that are associated with Gpnmb-p as a soluble osteogenic factor versus when it is applied as
a matricellular in enhancing OB differentiation/function and angiogenic response. (3) To evaluate efficacy and
safety of Gpnmb-hydrogels in bone regeneration. In this aim, we will apply the spinal fusion model in rats
(osteoporotic and non-osteoporotic) to evaluate in-vivo efficacy of Gpnmb-p-hydrogels. The project will provide
valuable evaluation of Gpnmb-hydrogels as a novel therapeutic strategy for bone regeneration with the potential
to serve as an alternative to autogenous bone graft. Mechanistic assessment of new and innovative therapeutic
targets of Gpnmb-p could have a broad therapeutic applicability.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><Adhesions><Amino Acids><Anabolic Agents><Attention><Autologous><Binding><Bleeding><Blood donor><Bone Diseases><Bone Formation><Bone Grafting><Bone Growth><Bone Injury><Bone Morphogenetic Protein Gene><Bone Morphogenetic Proteins><Bone Regeneration><Bone Transplantation><Cell Communication and Signaling><Cell Signaling><Clinical><Common Rat Strains><Complementary DNA><Coupled><Diffusion><Dihydroxyethanes><Dose><Drug Delivery><Drug Delivery Systems><Ectopic Ossification><Effectiveness><Ensure><Ethanediols><Ethylene Glycols><Evaluation><Fracture Healing><Future><Gel><Gene Expression><Glycoproteins><Goals><Hemorrhage><Heterotopic Ossification><Histology><Hydrogels><In Situ><Inflammation><Inflammatory><Injections><Integral Membrane Protein><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Kinetics><Lateral><Liquid substance><Malignant Melanoma><Mediating><Melanoma><Metabolic Glycosylation><Mice><Mice Mammals><Modeling><Molecular Interaction><Molecular Target><Molecular Weight><Monoethylene Glycol><Morbidity><Morbidity - disease rate><Murine><Mus><Non-metastatic><Nonmetastatic><Operative Procedures><Operative Surgical Procedures><Osteoblasts><Osteogenesis><Osteoporotic><Pathologic Ossification><Pathological Ossification><Peptides><Physiologic><Physiological><Post-Menopause><Post-Operative><Post-menopausal Period><Postmenopausal Period><Postmenopause><Postoperative><Postoperative Period><Procedures><Property><Proteins><Radiography><Rat><Rats Mammals><Rattus><Receptor Protein><Recombinants><Regimen><Roentgenography><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Site><Spinal Fusion><Spondylosyndeses><Surgical><Surgical Interventions><Surgical Procedure><System><Temperature><Therapeutic><Therapeutic Agents><Therapeutic Uses><Time><Transmembrane Protein><Transmembrane Protein Gene><Treatment outcome><Work><X-ray microtomography><Xray microtomography><after menopause><aminoacid><angiogenesis><biocompatibility><biological signal transduction><biomaterial compatibility><biomechanical analyses><biomechanical analysis><biomechanical assessment><biomechanical characterization><biomechanical evaluation><biomechanical measurement><biomechanical profiling><biomechanical test><blood loss><bone><bone disorder><bone fracture healing><bone fracture repair><bone morphogenic protein><bone tissue formation><bone transplant><cDNA><clinical applicability><clinical application><comparable efficacy><comparative efficacy><compare efficacy><controlled release><copolymer><cost><determine efficacy><diffused><diffuses><diffusing><diffusions><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><ethylene glycol><evaluate efficacy><examine efficacy><expectation><extracellular><fabrication cost><fluid><following menopause><fracture repair><glycoprotein NMB><glycosylation><gpNMB><improved><in vivo><innovate><innovation><innovative><interest><liquid><manufacturing cost><micro CT><micro computed tomography><microCT><microtomography><mutant><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><osteoactivin><osteoblast cell differentiation><osteoblast differentiation><osteoblastic differentiation><osteogenic><past menopause><post-menopausal><postmenopausal><postmenopausal status><protein B><radiologic imaging><radiological imaging><receptor><regenerate bone><regeneration based therapy><regeneration therapy><regenerative><regenerative approach><regenerative strategy><regenerative technique><regenerative therapeutics><regenerative therapy><response><side effect><success><surgery><therapeutic target><therapeutically effective><treatment strategy>