Abstract
The importance of canonical transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling during cartilage and joint development is well established, but the necessity for noncanonical (SMAD-independent) signaling during these processes is largely unknown. TGF-β activated kinase 1 (TAK1) is a MAP3K activated by TGF-β, BMP, and other mitogen-activated protein kinase (MAPK) signaling components. We set out to define the potential role for noncanonical, TAK1-mediated signaling in cartilage and joint development via deletion of Tak1 in chondrocytes (Col2Cre;Tak1f/f) and the developing limb mesenchyme (Prx1Cre;Tak1f/f). Deletion of Tak1 in chondrocytes resulted in novel embryonic developmental cartilage defects including decreased chondrocyte proliferation, reduced proliferating chondrocyte survival, delayed onset of hypertrophy, reduced Mmp13 expression, and a failure to maintain interzone cells of the elbow joint, which were not observed previously in another Col2Cre;Tak1f/f model. Deletion of Tak1 in limb mesenchyme resulted in widespread joint fusions likely owing to the differentiation of interzone cells to the chondrocyte lineage. The Prx1Cre;Tak1f/f model also allowed us to identify novel columnar chondrocyte organization and terminal maturation defects owing to the interplay between chondrocytes and the surrounding mesenchyme. Furthermore, both our in vivo models and in vitro cell culture studies demonstrate that loss of Tak1 results in impaired activation of the downstream MAPK target p38, as well as diminished activation of the BMP/SMAD signaling pathway. Taken together, these data demonstrate that TAK1 is a critical regulator of both MAPK and BMP signaling and is necessary for proper cartilage and joint development. © 2010 American Society for Bone and Mineral Research.
Highlights
Limb development is a complicated process culminating in the formation of a highly functional limb skeleton composed of cartilage, bone, connective tissues, and mobile joints
Critical differences between the two models include the ability of their Tak1Col2 mutants to survive postnatally for 2 to 3 weeks, whereas our Tak1Col2 mutants die prior to birth, and the timing for the onset of cartilage phenotypes.[34]. Compared with the previous study, it is likely that our mice exhibited an earlier deletion of the Tak1 floxed alleles owing to the use of a different Col2Cre transgenic mouse[36,47] and produced a more profound and slightly different embryonic cartilage phenotype.[34]. Interestingly, our Tak1Col2 mutants displayed a dramatic phenotype during early stages of chondrocyte maturation (E14.5) that appeared to diminish progressively at later stages of development (E18.5)
This is highlighted by the dramatic decrease in chondrocyte proliferation ($40%) that was later restored to near-wild-type levels even in the presence of continued TGF-b activated kinase 1 (TAK1) expression
Summary
Limb development is a complicated process culminating in the formation of a highly functional limb skeleton composed of cartilage, bone, connective tissues, and mobile joints. The limb skeleton originally derives from mesenchymal cells of the lateral-plate mesoderm that migrate, condense, proliferate, differentiate, and undergo terminal maturation. Mesenchymal cells outside interzone regions complete the process of chondrogenesis primarily through the activities of Sox family transcription factors—Sox, Sox, and Sox6.(9,10) After initial formation of the individual cartilage rudiments, coupled processes of chondrocyte proliferation and maturation are responsible for longitudinal growth. Chondrocyte proliferation serves as the initial driving force of longitudinal growth, but proliferating cells near the center of cartilage elements withdraw from the cell cycle and undergo chondrocyte maturation or hypertrophic differentiation. Completion of chondrocyte maturation is necessary for proper vascular invasion, establishment of the marrow cavity, and normal growth plate development
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
