title: Knockdown of Ggps1 in chondrocyte expedites fracture healing by accelerating the progression of endochondral ossification in mice.
abstract: Bone fracture healing is achieved through the proliferation and differentiation of stem cells, while bone marrow stem cells (BMSCs) contribute to endochondral ossification. During fracture healing, mesenchymal progenitor cells first form a cartilaginous blastema that becomes vascularized to recruit precursor cells of osteoblasts through the bone morphogenetic protein 2 (Bmp2)/Smad-dependent Runx2 pathway. Statins deplete geranylgeranyl diphosphate (GGPP), which participates in the regulation of BMSCs differentiation, through the inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, leading to impaired protein geranylgeranylation, which strongly impacts the bone synthesis induced by Bmp2. Accordingly, we would like to investigate the role of geranylgeranyl diphosphate synthase 1 (Ggps1) in bone fracture via endochondral ossification in mice. We used a Cre-loxP system, namely the tamoxifen-inducible Collagen 2-CreERT2Ggps1fl/fl, to eliminate specifically the Ggps1 activity in chondrocytes of 8-10-week-old mice. We found that the endochondral bone formation, calcification and vasculogenesis of the bony callus were accelerated in fractures in Ggps1-/-mice. Together, the results of this study confirm that the specific deletion of Ggps1, using the Collagen 2-CreERT2mice, will accelerate the fracture healing process by activating the Bmp2/Smad-dependent Runx2 pathway. In addition, we managed to improve the fracture healing process by inhibiting the Ggps1 activity and its related products with statin drugs.
authors.affiliation: Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.|Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China.
authors.forename: Bingyang
authors.initials: B
authors.lastname: Dai
authors.affiliation: Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.
authors.forename: Qiangqiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.|Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.|Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ge
authors.affiliation: The School of Medicine, Nanjing University, Nanjing, 210093, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.|Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China.
authors.forename: Kaijia
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.|Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: The School of Medicine, Nanjing University, Nanjing, 210093, People's Republic of China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China. tenghj@nicemice.cn.
authors.forename: Huajian
authors.initials: H
authors.lastname: Teng
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing, 210093, People's Republic of China. licj@nju.edu.cn.
authors.forename: Chaojun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China. qingj@nju.edu.cn.|Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China. qingj@nju.edu.cn.|Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China. qingj@nju.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002146:Bony Callus / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000172:deficiency / Q000378:metabolism*; D005269:Femur / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D017102:Fracture Healing / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010012:Osteogenesis / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; C495428:Ggps1 protein, mouse; D019394:Ki-67 Antigen; D009097:Multienzyme Complexes; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D051231:Farnesyltranstransferase
keywords: Bone fracture; Endochondral ossification; Geranylgeranyl diphosphate synthase 1; Intramembranous ossification