title: Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling.
abstract: In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-catenin(Prx1ER) conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing process in CD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-catenin(Prx1ER) conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention.
authors.affiliation: Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China.
authors.forename: Hongting
authors.initials: H
authors.lastname: Jin
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Baoli
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA; Liaoning University of Traditional Chinese Medicine, Liaoning, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA; Liaoning University of Traditional Chinese Medicine, Liaoning, China.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Xie
authors.affiliation: Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Mao
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Dong
authors.affiliation: Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Hua-Zhu
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Babij
authors.affiliation: Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China; Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China. Electronic address: peijiantongzy@126.com.
authors.forename: Peijian
authors.initials: P
authors.lastname: Tong
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA. Electronic address: di_chen@rush.edu.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000187:drug effects; D002146:Bony Callus / Q000187:drug effects / Q000473:pathology; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D017102:Fracture Healing / Q000187:drug effects*; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011859:Radiography; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000906:Antibodies; D015415:Biomarkers; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051176:beta Catenin; C045073:Cre recombinase; D019426:Integrases
keywords: Conditional knockout; Dkk1-Ab; Fracture healing; Mesenchymal progenitor cells; β-Catenin