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

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 

作者机构：Department of Orthopedic SurgeryJohns Hopkins University School of MedicineRoss BuildingRoom 229720 Rutland AveBaltimoreMDUSA State Key Laboratory of Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina Department of Spine SurgeryXiangya 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 TraumatologyDepartment of Spinal SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Department of PediatricsJohns Hopkins University School of MedicineRoss BuildingRoom 229720 Rutland AveBaltimoreMDUSA The Russell H.Morgan Department of Radiology and Radiological ScienceJohns Hopkins University School of MedicineRoss BuildingRoom 229720 Rutland AveBaltimoreMDUSA Faculty of Computer ScienceCollege of Information Science and EngineeringXiangya HospitalCentral South UniversityChangshaChina Department of Physiology and PharmacologySchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada Department of Sports MedicineXiangya HospitalCentral South UniversityChangshaChina 

出 版 物：《Bone Research》 (骨研究（英文版）)

年 卷 期：2018年第6卷第3期

页      面：252-265页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100210[医学-外科学(含：普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学] 

基　　金：supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers AR071432 and AR063943 

主　　题：disc injection integrin cells iPTH effect TGF-β human 

摘      要：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.