title: Interaction of TGFβ and BMP signaling pathways during chondrogenesis.
abstract: TGFβ and BMP signaling pathways exhibit antagonistic activities during the development of many tissues. Although the crosstalk between BMP and TGFβ signaling pathways is well established in bone development, the relationship between these two pathways is less well defined during cartilage development and postnatal homeostasis. We generated hypomorphic mouse models of cartilage-specific loss of BMP and TGFβ signaling to assess the interaction of these pathways in postnatal growth plate homeostasis. We further used the chondrogenic ATDC5 cell line to test effects of BMP and TGFβ signaling on each other's downstream targets. We found that conditional deletion of Smad1 in chondrocytes resulted in a shortening of the growth plate. The addition of Smad5 haploinsufficiency led to a more severe phenotype with shorter prehypertrophic and hypertrophic zones and decreased chondrocyte proliferation. The opposite growth plate phenotype was observed in a transgenic mouse model of decreased chondrocytic TGFβ signaling that was generated by expressing a dominant negative form of the TGFβ receptor I (ΔTβRI) in cartilage. Histological analysis demonstrated elongated growth plates with enhanced Ihh expression, as well as an increased proliferation rate with altered production of extracellular matrix components. In contrast, in chondrogenic ATDC5 cells, TGFβ was able to enhance BMP signaling, while BMP2 significantly reduces levels of TGF signaling. In summary, our data demonstrate that during endochondral ossification, BMP and TGFβ signaling can have antagonistic effects on chondrocyte proliferation and differentiation in vivo. We also found evidence of direct interaction between the two signaling pathways in a cell model of chondrogenesis in vitro.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Bettina
authors.initials: B
authors.lastname: Keller
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.forename: Terry
authors.initials: T
authors.lastname: Bertin
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D055395:Bone Morphogenetic Protein 1; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002356:Cartilage / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D020219:Chondrogenesis; D006132:Growth Plate / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D020239:Receptor Cross-Talk / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1