PTH 1-34 Ameliorates the Osteopenia and Delayed Healing of Stabilized Tibia Fracture in Mice with Achondroplasia Resulting from Gain-Of-Function Mutation of FGFR3.
Hangang Chen, Xianding Sun, Liangjun Yin, Shuai Chen, Ying Zhu, Junlan Huang, Wanling Jiang, Bo Chen, Ruobin Zhang, Lin Chen, Mao Nie, Yangli Xie, Zhongliang Deng
Author Information
Hangang Chen: Department of Orthopedic Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Xianding Sun: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Liangjun Yin: Department of Orthopedic Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Shuai Chen: Department of Orthopedic Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Ying Zhu: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Junlan Huang: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Wanling Jiang: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Bo Chen: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Ruobin Zhang: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Lin Chen: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Mao Nie: Department of Orthopedic Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Yangli Xie: Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Zhongliang Deng: Department of Orthopedic Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Bone Fracture healing is processed through multiple stages including the cartilaginous callus formation and its transition to bony callus. FGFR3 negatively regulates chondrogenesis and enhances osteogenesis during skeleton development. We previously found in Mice carrying gain-of-function mutation of FGFR3 that FGFR3 delays the healing of un-stabilized Fracture that heals mainly through endochondral ossification. Since Fracture is regularly treated in clinics with rigid fixation, and stabilized Fracture is healed largely through intramembranous ossification, we asked whether FGFR3, a key regulator of osteogenesis, also affect the regeneration of stabilized Fracture. We found that gain-of-function mutation of FGFR3 inhibits the initiation of chondrogenesis and the subsequent bone formation. We further studied whether PTH1-34 can improve the Osteopenia and delayed healing of the stabilized Tibia Fracture in Mice with Achondroplasia. Fracture healing was evaluated by radiography, micro-CT, biomechanical tests, histology, and real-time polymerase chain reaction (RT-PCR) analysis. We found that PTH 1-34 can alleviate the decreased bone mass and compromised architecture in ACHMice. Histological analysis revealed that administration of PTH1-34 increased the size of both the total callus and cartilaginous callus at 14 days after the surgery in ACHMice. RT-PCR data suggested that systemic PTH1-34 accelerated the initiation of chondrogenesis and chondrocyte maturation (earlier and higher levels of expression of chondrogenesis related markers) and enhanced the osteogenic differentiation in the Fracture callus in ACHMice. These results indicate that the PTH1-34 administration resulted in an enhanced callus formation during Bone Fracture healing in ACHMice, which is at least in part mediated by an increase of cartilaginous callus at early stage and the promotion of bone formation in bony callus. In summary, in this study we revealed that FGFR3 delays the regeneration of stabilized Fracture by inhibiting both the chondrogenesis and osteogenesis, and PTH1-34 treatment can improve the dysregulated bone metabolism and delayed bone injury healing resulting from gain-of-function mutation of FGFR3.
References
Genes Dev. 2002 Jun 15;16(12):1446-65
[PMID: 12080084]
