Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis

Nat Med. 2013 Jun;19(6):704-12. doi: 10.1038/nm.3143. Epub 2013 May 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / physiology

Substances

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