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: Gehua Zhen, Chunyi Wen, Xiaofeng Jia, Yu Li, Janet L Crane, Simon C Mears, Frederic B Askin, Frank J Frassica, Weizhong Chang, Jie Yao, John A Carrino, Andrew Cosgarea, Dmitri Artemov, Qianming Chen, Zhihe Zhao, Xuedong Zhou, Lee Riley, Paul Sponseller, Mei Wan, William Weijia Lu, Xu Cao
• Journal: Nature medicine (Nat Med) Vol. 19 Issue 6 Pg. 704-12 (Jun 2013) ISSN: 1546-170X [Electronic] United States
• PMID: 23685840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Animals
• Bone and Bones (metabolism)
• Cartilage (pathology)
• Cells, Cultured
• Male
• Mesenchymal Stem Cells (physiology)
• Mice
• Mice, Inbred C57BL
• Osteoarthritis (therapy)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Rats
• Rats, Inbred Lew
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Signal Transduction (physiology)
• Transforming Growth Factor beta (analysis, antagonists & inhibitors, physiology)