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Ciliary parathyroid hormone signaling activates transforming growth factor-βto maintain intervertebral disc homeostasis during aging

引用

Bone Research 2018年第3期6卷 252-265页

作者： Liwei Zheng Yong Cao Shuangfei Ni Huabin Qi Zemin Ling Xin Xu Xuenong Zou Tianding Wu Ruoxian Deng Bo Hu Bo Gao Hao Chen Yusheng Li Jianxi Zhu Francis Tintani Shadpour Demehri Amit Jain khaled m.kebaish Shenghui Liao Cheryle A.Séguin Janet L.Crane mei Wan Hongbin Lu Paul D.Sponseller Lee H.RileyIII Xuedong Zhou Jianzhong Hu Xu Cao Department of Orthopedic Surgery Johns Hopkins University School of MedicineRoss BuildingRoom 229720 Rutland AveBaltimoreMDUSA State Key Laboratory of Oral Diseases West China Hospital of StomatologySichuan UniversityChengduChina Department of Spine Surgery Xiangya HospitalCentral South UniversityChangshaChina Center of Bone metabolism and Repair(CBmR) Trauma CenterInstitute of Surgery ResearchDaping HospitalThird Military Medical UniversityChongqingChina Guangdong Provincial Key Laboratory of Orthopedics and Traumatology Department of Spinal SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Department of Pediatrics Johns Hopkins University School of MedicineRoss BuildingRoom 229720 Rutland AveBaltimoreMDUSA The Russell H.morgan Department of Radiology and Radiological Science Johns Hopkins University School of MedicineRoss BuildingRoom 229720 Rutland AveBaltimoreMDUSA Faculty of Computer Science College of Information Science and EngineeringXiangya HospitalCentral South UniversityChangshaChina Department of Physiology and Pharmacology Schulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada Department of Sports medicine Xiangya HospitalCentral South UniversityChangshaChina

Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.

关键词： disc injection integrin cells iPTH effect TGF-β human

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