TGF-β signaling is essential for joint morphogenesis

Anna Spagnoli, Lynda O'Rear, Ronald L. Chandler, Froilan Granero-Molto, Douglas P. Mortlock, Agnieszka E. Gorska, Jared A. Weis, Lara Longobardi, Anna Chytil, Kimberly Shimer, Harold L. Moses

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Abstract

Despite its clinical significance, joint morphogenesis is still an obscure process. In this study, we determine the role of transforming growth factor β (TGF-β) signaling in mice lacking the TGF-β type II receptor gene (Tgfbr2) in their limbs (Tgfbr2PRX-1KO). In Tgfbr2 PRX-1KO mice, the loss of TGF-β responsiveness resulted in the absence of interphalangeal joints. The Tgfbr2Prx1KO joint phenotype is similar to that in patients with symphalangism (SYM1-OMIM185800). By generating a Tgfbr2-green fluorescent protein-β-GEO-bacterial arti-ficial chromosome β-galactosidase reporter transgenic mouse and by in situ hybridization and immunofluorescence, we determined that Tgfbr2 is highly and specifically expressed in developing joints. We demonstrated that in Tgfbr2 PRX-1KO mice, the failure of joint interzone development resulted from an aberrant persistence of differentiated chondrocytes and failure of Jagged-1 expression. We found that TGF-β receptor II signaling regulates Noggin, Wnt9a, and growth and differentiation factor-5 joint morphogenic gene expressions. In Tgfbr2PRX-1KO growth plates adjacent to interphalangeal joints, Indian hedgehog expression is increased, whereas Collagen 10 expression decreased. We propose a model for joint development in which TGF-β signaling represents a means of entry to initiate the process.

Original languageEnglish (US)
Pages (from-to)1105-1117
Number of pages13
JournalJournal of Cell Biology
Volume177
Issue number6
DOIs
StatePublished - Jun 18 2007

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Spagnoli, A., O'Rear, L., Chandler, R. L., Granero-Molto, F., Mortlock, D. P., Gorska, A. E., Weis, J. A., Longobardi, L., Chytil, A., Shimer, K., & Moses, H. L. (2007). TGF-β signaling is essential for joint morphogenesis. Journal of Cell Biology, 177(6), 1105-1117. https://doi.org/10.1083/jcb.200611031