Functional block of IL-17 cytokine promotes bone healing by augmenting FOXO1 and ATF4 activity in cortical bone defect model.
We determine the effect of interleukin (IL)-17 neutralizing antibody on new bone regeneration. Anti-IL-17 antibody promoted new bone regeneration in cortical bone defect model by augmenting FOXO1 and ATF4 activity thereby decreasing oxidative stress. Our study demonstrates the bone healing and regeneration potential of neutralizing IL-17antibody in osteoporotic fractures.



The immune system plays important role in the fracture healing process. However, fracture healing is prolonged in disorders associated with systemic inflammation. Fracture healing is decelerated in osteoporosis, condition linked with systemic inflammation. Bone regeneration therapies like recombinant human BMP2 are associated with serious side effects. Studies have been carried out where agents like denosumab and infliximab enhance bone regeneration in osteoporotic conditions. Our previous studies show the osteoprotective and immunoprotective effects of neutralizing IL-17 antibody. Here, we determine the effect of IL-17 neutralizing antibody on new bone regeneration and compare its efficacy with known osteoporotic therapies.



For the study, female BALB/c mice were ovariectomized or sham operated and left for a month followed by a 0.6-mm drill-hole injury in femur mid-diaphysis. The treatment was commenced next day onwards with anti-IL-17, anti-RANKL (Receptor activator of nuclear factor kappa-B ligand), parathyroid hormone (PTH), or alendronate for a period of 3, 10, or 21 days. Animals were then autopsied, and femur bones were dissected out for micro-CT scanning, confocal microscopy, and gene and protein expression studies.



Micro-CT analysis showed that anti-IL-17 antibody promoted bone healing at days 10 and 21, and the healing effect observed was significantly better than Ovx, anti-RANKL antibody, and ALN, and equal to PTH. Anti-IL-17 also enhanced new bone regeneration as assessed by calcein-labeling studies. Additionally, anti-IL-17 therapy enhanced expression of osteogenic markers and decreased oxidative stress at the injury site.



Overall, our study demonstrates bone healing and regeneration potential of neutralizing IL-17 antibody in osteoporotic fractures.
Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow, India.
M
M
Dixit
Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow, India.
K B
KB
Singh
Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow, India.
R
R
Prakash
Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow, India. divya_singh@cdri.res.in.
D
D
Singh
D051701:Activating Transcription Factor 4 / Q000276:immunology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000276:immunology; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001861:Bone Regeneration / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005264:Femoral Fractures / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D000071161:Forkhead Box Protein O1 / Q000276:immunology; D017102:Fracture Healing / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008807:Mice, Inbred BALB C; D058866:Osteoporotic Fractures / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D010052:Ovariectomy; D018384:Oxidative Stress / Q000276:immunology / Q000502:physiology; D014945:Wound Healing / Q000276:immunology / Q000502:physiology; D055114:X-Ray Microtomography
C081452:Atf4 protein, mouse; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D020381:Interleukin-17; D051701:Activating Transcription Factor 4
Bone healing; Bone mineral density; Bone regeneration; Bone strength; Drill-hole injury; Immune system; Osteoporosis