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Principal Investigator: Jianjun Guan
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $548,332
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
ABSTRACT
Fracture nonunion poses a significant clinical problem. In the United States, approximately 1.6 million bone
fractures encounter prolonged healing or nonunion each year. Fracture nonunion treatment usually involves
complicated and massive procedures in practice, and sometimes needs multiple surgeries, therefore increases
the cost of health care and results in marked patient disability. The major population bearing with these clinical
complications are patients with inflammatory conditions, e.g, elder patients, smoking, diabetic or rheumatoid
arthritis (RA) patients, highlighting the potential deleterious role of chronic systemic inflammation in fracture
r epair.
The overarching hypothesis of this proposal is that chronic inflammation results in fracture nonunion
through Dnmt3b downregulation mediated angiogenesis defect, and local delivery of OPN and CXCL12 restores
angiogenesis and fracture repair under inflammatory conditions. This hypothesis is supported by our preliminary
data wherein we show that Dnmt3b is highly expressed in fracture callus during fracture repair and Dnmt3b is
the major DNA methyltransferase (Dnmt) responsive to cytokines in MPCs. Relevant to our proposal, we provide
evidence that inflammatory signals inhibit Dnmt3b in an NF-κB-dependent manner. Consistently, mice with
Dnmt3b loss-of-function (LOF) in chondrocytes display impaired angiogenesis and fracture repair; and Dnmt3b
gain-of-function (GOF) in chondrocytes shows protective effect from inflammation in vitro and accelerates
fracture repair in mice. Mechanistically, angiogenesis defect mediated by inflammation and Dnmt3b LOF
coincide with downregulation of OPN (Osteopontin) and CXCL12 (C-X-C Motif Chemokine Ligand 12) and
exogenous OPN and CXCL12 can restore angiogenesis capacity in vitro. To further examine the efficacy of local
delivery of OPN and CXCL12 in vivo, we have developed an optimized biomaterial sheet loaded with OPN and
CXCL12 and showed a robust angiogenesis process and a restoration of fracture union in RA mice.
Three main Specific Aims are proposed. Specific Aim 1 will delineate the mechanism by which
inflammation reduces angiogenesis via downregulating Dnmt3b during fracture repair. Specific Aim 2 will
determine the optimal release kinetics of OPN and CXCL12 on angiogenesis. Specific Aim 3 will determine the
therapeutic effect of sustained OPN and CXCL12 release on angiogenesis and fracture nonunion in mice. The
proposed studies will enhance our understanding of mechanisms by which systemic inflammation (via the NF-
κB pathway) affects the angiogenic process through Dnmt3b. This work will establish an important therapeutic
option to improve the angiogenesis and fracture healing.
Terms: <2aR phosphoprotein I><2ar peptide><Acceleration><Address><Affect><Atrophic Arthritis><Beta Proprotein Interleukin 1><Biocompatible Materials><Biomaterials><Blood Serum><Bone callus><Bony Callus><Callus><Cell Body><Cell Communication and Signaling><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Chemotactic Cytokines><Chondrocytes><Chronic><Clinical><Clinical Research><Clinical Study><DNA Methylation><DNA Methyltransferase><DNA Methyltransferase 3B><DNA Modification Methylases><DNA Modification Methyltransferases><DNA-Methyltransferases><DNMT3B gene><DNMT3b><Data><Defect><Diabetes Mellitus><Disease><Disorder><Dnmt><Down-Regulation><Endothelial Cells><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Eta-1 protein><Eta-1-Op protein><Failure><Fracture><Fracture Healing><Gene Expression><Health Care Costs><Health Costs><Healthcare Costs><Homologous Chemotactic Cytokines><Human><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Impairment><In Vitro><Inflammation><Inflammatory><Intercrines><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intracellular Communication and Signaling><K/BxN><K/BxN model><KBxN><Kinetics><Knowledge><Ligands><Mediating><Methylation><Mice><Mice Mammals><Modern Man><Modification Methylases><Molecular><Murine><Mus><Operative Procedures><Operative Surgical Procedures><Pathway interactions><Patients><Population><Preinterleukin 1 Beta><Procedures><Process><Rheumatoid Arthritis><Role><SIS cytokines><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Site-Specific DNA-methyltransferase><Smoking><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><Therapeutic><Therapeutic Effect><Therapeutic Intervention><Tube><United States><Work><angiogenesis><biodegradable scaffold><biological material><biological signal transduction><bone fracture><bone fracture healing><bone fracture repair><bone sialoprotein 1><bone sialoprotein I><cell motility><chemoattractant cytokine><chemokine><co-morbid><co-morbidity><comorbidity><cytokine><determine efficacy><diabetes><diabetic><disability><early T-lympocyte activation-1 protein><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elderly patient><epigenetically><epigenome><evaluate efficacy><examine efficacy><experience><fracture repair><gain of function><hDNA methyltransferase 3b><healing><improved><in vivo><intervention therapy><loss of function><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><older patient><osteopontin><pathway><pharmacologic><protective effect><restoration><rheumatic arthritis><scaffold><scaffolding><secreted phosphoprotein 1><sialoprotein 1><social role><surgery><systemic inflammation><systemic inflammatory response><therapeutically effective>