title: Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis.
abstract: Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Gehua
authors.initials: G
authors.lastname: Zhen
authors.forename: Chunyi
authors.initials: C
authors.lastname: Wen
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jia
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Janet L
authors.initials: JL
authors.lastname: Crane
authors.forename: Simon C
authors.initials: SC
authors.lastname: Mears
authors.forename: Frederic B
authors.initials: FB
authors.lastname: Askin
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Frassica
authors.forename: Weizhong
authors.initials: W
authors.lastname: Chang
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.forename: John A
authors.initials: JA
authors.lastname: Carrino
authors.forename: Andrew
authors.initials: A
authors.lastname: Cosgarea
authors.forename: Dmitri
authors.initials: D
authors.lastname: Artemov
authors.forename: Qianming
authors.initials: Q
authors.lastname: Chen
authors.forename: Zhihe
authors.initials: Z
authors.lastname: Zhao
authors.forename: Xuedong
authors.initials: X
authors.lastname: Zhou
authors.forename: Lee
authors.initials: L
authors.lastname: Riley
authors.forename: Paul
authors.initials: P
authors.lastname: Sponseller
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
authors.forename: William Weijia
authors.initials: WW
authors.lastname: Lu
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002356:Cartilage / Q000473:pathology; D002478:Cells, Cultured; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II