title: Excessive Activation of TGFβ by Spinal Instability Causes Vertebral Endplate Sclerosis.
abstract: Narrowed intervertebral disc (IVD) space is a characteristic of IVD degeneration. EP sclerosis is associated with IVD, however the pathogenesis of EP hypertrophy is poorly understood. Here, we employed two spine instability mouse models to investigate temporal and spatial EP changes associated with IVD volume, considering them as a functional unit. We found that aberrant mechanical loading leads to accelerated ossification and hypertrophy of EP, decreased IVD volume and increased activation of TGFβ. Overexpression of active TGFβ in CED mice showed a similar phenotype of spine instability model. Administration of TGFβ Receptor I inhibitor attenuates pathologic changes of EP and prevents IVD narrowing. The aberrant activation of TGFβ resulting in EPs hypertrophy-induced IVD space narrowing provides a pharmacologic target that could have therapeutic potential to delay DDD.
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.|Institute of Spine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, P. R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Bian
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.|State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Khaled
authors.initials: K
authors.lastname: Kebaish
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.|Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Crane
authors.affiliation: Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Lee H
authors.initials: LH
authors.lastname: Riley
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Sponseller
authors.affiliation: Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
authors.forename: X Edward
authors.initials: XE
authors.lastname: Guo
authors.affiliation: Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
authors.forename: Willian Weijia
authors.initials: WW
authors.lastname: Lu
authors.affiliation: Institute of Spine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, P. R. China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007403:Intervertebral Disc / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012598:Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000076182:Sp7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D016474:Weight-Bearing
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; C577485:Nes protein, mouse; D064231:Nestin; D018125:Receptors, Transforming Growth Factor beta; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I