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Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice.
Arthritis Rheum. 2013 Dec; 65(12):3107-19.AR

Abstract

OBJECTIVE

While transforming growth factor β (TGFβ) signaling plays a critical role in chondrocyte metabolism, the TGFβ signaling pathways and target genes involved in cartilage homeostasis and the development of osteoarthritis (OA) remain unclear. Using an in vitro cell culture method and an in vivo mouse genetic approach, we undertook this study to investigate TGFβ signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling.

METHODS

TGFβ receptor type II (TGFβRII)-conditional knockout (KO) (TGFβRII(Col2ER)) mice were generated by breeding TGFβRII(flox/flox) mice with Col2-CreER-transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGFβ signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling, TGFβRII/matrix metalloproteinase 13 (MMP-13)- and TGFβRII/ADAMTS-5-double-KO mice were generated and analyzed.

RESULTS

Inhibition of TGFβ signaling (deletion of the Tgfbr2 gene in chondrocytes) resulted in up-regulation of Runx2, Mmp13, and Adamts5 expression in articular cartilage tissue and progressive OA development in TGFβRII(Col2ER) mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGFβ signaling. Treatment of TGFβRII(Col2ER) mice with an MMP-13 inhibitor also slowed OA progression.

CONCLUSION

Mmp13 and Adamts5 are critical downstream target genes involved in the TGFβ signaling pathway during the development of OA.

Links

PMC Free PDF

Authors+Show Affiliations

Shen J
Rush University Medical Center, Chicago, Illinois; University of Rochester School of Medicine, Rochester, New York.
Li J
No affiliation info available
Wang B
No affiliation info available
Jin H
No affiliation info available
Wang M
No affiliation info available
Zhang Y
No affiliation info available
Yang Y
No affiliation info available
Im HJ
No affiliation info available
O'Keefe R
No affiliation info available
Chen D
No affiliation info available

MeSH

ADAM ProteinsADAMTS5 ProteinAnimalsCartilage, ArticularChondrocytesCore Binding Factor Alpha 2 SubunitDisease ProgressionMatrix Metalloproteinase 13MiceMice, KnockoutOsteoarthritisPhenotypeProtein Serine-Threonine KinasesReceptor, Transforming Growth Factor-beta Type IIReceptors, Transforming Growth Factor betaSignal TransductionUp-Regulation

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23982761

Citation

Shen, Jie, et al. "Deletion of the Transforming Growth Factor Β Receptor Type II Gene in Articular Chondrocytes Leads to a Progressive Osteoarthritis-like Phenotype in Mice." Arthritis and Rheumatism, vol. 65, no. 12, 2013, pp. 3107-19.
Shen J, Li J, Wang B, et al. Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum. 2013;65(12):3107-19.
Shen, J., Li, J., Wang, B., Jin, H., Wang, M., Zhang, Y., Yang, Y., Im, H. J., O'Keefe, R., & Chen, D. (2013). Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis and Rheumatism, 65(12), 3107-19. https://doi.org/10.1002/art.38122
Shen J, et al. Deletion of the Transforming Growth Factor Β Receptor Type II Gene in Articular Chondrocytes Leads to a Progressive Osteoarthritis-like Phenotype in Mice. Arthritis Rheum. 2013;65(12):3107-19. PubMed PMID: 23982761.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. AU - Shen,Jie, AU - Li,Jia, AU - Wang,Baoli, AU - Jin,Hongting, AU - Wang,Meina, AU - Zhang,Yejia, AU - Yang,Yunzhi, AU - Im,Hee-Jeong, AU - O'Keefe,Regis, AU - Chen,Di, PY - 2012/12/24/received PY - 2013/8/1/accepted PY - 2013/8/29/entrez PY - 2013/8/29/pubmed PY - 2014/1/28/medline SP - 3107 EP - 19 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 65 IS - 12 N2 - OBJECTIVE: While transforming growth factor β (TGFβ) signaling plays a critical role in chondrocyte metabolism, the TGFβ signaling pathways and target genes involved in cartilage homeostasis and the development of osteoarthritis (OA) remain unclear. Using an in vitro cell culture method and an in vivo mouse genetic approach, we undertook this study to investigate TGFβ signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling. METHODS: TGFβ receptor type II (TGFβRII)-conditional knockout (KO) (TGFβRII(Col2ER)) mice were generated by breeding TGFβRII(flox/flox) mice with Col2-CreER-transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGFβ signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling, TGFβRII/matrix metalloproteinase 13 (MMP-13)- and TGFβRII/ADAMTS-5-double-KO mice were generated and analyzed. RESULTS: Inhibition of TGFβ signaling (deletion of the Tgfbr2 gene in chondrocytes) resulted in up-regulation of Runx2, Mmp13, and Adamts5 expression in articular cartilage tissue and progressive OA development in TGFβRII(Col2ER) mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGFβ signaling. Treatment of TGFβRII(Col2ER) mice with an MMP-13 inhibitor also slowed OA progression. CONCLUSION: Mmp13 and Adamts5 are critical downstream target genes involved in the TGFβ signaling pathway during the development of OA. SN - 1529-0131 UR - https://www.unboundmedicine.com/medline/citation/23982761/Deletion_of_the_transforming_growth_factor_β_receptor_type_II_gene_in_articular_chondrocytes_leads_to_a_progressive_osteoarthritis_like_phenotype_in_mice_ DB - PRIME DP - Unbound Medicine ER -