TAK1 Regulates Cartilage and Joint Development via the MAPK and BMP Signaling Pathways

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

[1]  Min Xie,et al.  TAK1 is an essential regulator of BMP signalling in cartilage , 2009, The EMBO journal.

[2]  K. Retting,et al.  BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation , 2009, Development.

[3]  D. Moore,et al.  Reduced limb length and worsened osteoarthritis in adult mice after genetic inhibition of p38 MAP kinase activity in cartilage. , 2008, Arthritis and rheumatism.

[4]  Masahiro Iwamoto,et al.  A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. , 2008, Developmental biology.

[5]  R. Serra,et al.  Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. , 2007, Developmental biology.

[6]  Fanxin Long,et al.  Tamoxifen-inducible gene deletion reveals a distinct cell type associated with trabecular bone, and direct regulation of PTHrP expression and chondrocyte morphology by Ihh in growth region cartilage. , 2007, Developmental biology.

[7]  Takashi Nakamura,et al.  Transcription factor ERG and joint and articular cartilage formation during mouse limb and spine skeletogenesis. , 2007, Developmental biology.

[8]  Jae-Chang Jung,et al.  BMP-2-enhanced chondrogenesis involves p38 MAPK-mediated down-regulation of Wnt-7a pathway. , 2006, Molecules and cells.

[9]  R. Behringer,et al.  BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways , 2006, Development.

[10]  C. Hartmann,et al.  Role of canonical Wnt-signalling in joint formation. , 2006, European cells & materials.

[11]  Amitabha Bandyopadhyay,et al.  Genetic Analysis of the Roles of BMP2, BMP4, and BMP7 in Limb Patterning and Skeletogenesis , 2006, PLoS genetics.

[12]  Michael D. Schneider,et al.  Essential role of TAK1 in thymocyte development and activation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[13]  E. Schwarz,et al.  Transforming Growth Factor-β Stimulates Cyclin D1 Expression through Activation of β-Catenin Signaling in Chondrocytes* , 2006, Journal of Biological Chemistry.

[14]  A. Pitsillides,et al.  Differential regulation of GDF‐5 and FGF‐2/4 by immobilisation in ovo exposes distinct roles in joint formation , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[15]  S. Murakami,et al.  Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Fanxin Long,et al.  Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development , 2005, Development.

[17]  E. Schwarz,et al.  Smad3‐Deficient Chondrocytes Have Enhanced BMP Signaling and Accelerated Differentiation , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[18]  A. Hoffmann,et al.  Transforming Growth Factor-β-activated Kinase-1 (TAK1), a MAP3K, Interacts with Smad Proteins and Interferes with Osteogenesis in Murine Mesenchymal Progenitors*[boxs] , 2005, Journal of Biological Chemistry.

[19]  Xizhi Guo,et al.  Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. , 2005, Developmental cell.

[20]  Walter Birchmeier,et al.  Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. , 2005, Developmental cell.

[21]  D. Ovchinnikov,et al.  Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Ornitz,et al.  Sequential roles of Hedgehog and Wnt signaling in osteoblast development , 2004, Development.

[23]  H. Moses,et al.  Conditional deletion of the TGF-beta type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. , 2004, Developmental biology.

[24]  Z. Werb,et al.  Altered endochondral bone development in matrix metalloproteinase 13-deficient mice , 2004, Development.

[25]  D. Kingsley,et al.  BMP Receptor Signaling Is Required for Postnatal Maintenance of Articular Cartilage , 2004, PLoS biology.

[26]  L. Topol,et al.  Wnt/β-catenin signaling is sufficient and necessary for synovial joint formation , 2004 .

[27]  J. Rodríguez-León,et al.  A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. , 2004, Developmental biology.

[28]  C. Colnot,et al.  Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development. , 2004, Developmental biology.

[29]  W. Hozack,et al.  Transforming Growth Factor-β-mediated Chondrogenesis of Human Mesenchymal Progenitor Cells Involves N-cadherin and Mitogen-activated Protein Kinase and Wnt Signaling Cross-talk* , 2003, Journal of Biological Chemistry.

[30]  Di Chen,et al.  E3 Ubiquitin Ligase Smurf1 Mediates Core-binding Factor α1/Runx2 Degradation and Plays A Specific Role in Osteoblast Differentiation* , 2003, Journal of Biological Chemistry.

[31]  S. Dedhar,et al.  Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes , 2003, The Journal of cell biology.

[32]  J. Ninomiya-Tsuji,et al.  A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase* , 2003, The Journal of Biological Chemistry.

[33]  F. Beier,et al.  The Role of Activating Transcription Factor-2 in Skeletal Growth Control , 2003, The Journal of bone and joint surgery. American volume.

[34]  D. Kingsley,et al.  Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. , 2003, Developmental biology.

[35]  Marie-Christine Chaboissier,et al.  The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. , 2002, Genes & development.

[36]  I. Komuro,et al.  A role for bone morphogenetic protein signaling in cardiomyocyte differentiation. , 2002, Trends in cardiovascular medicine.

[37]  C. Tabin,et al.  Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer , 2002, Genesis.

[38]  V. Lefebvre,et al.  The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. , 2001, Developmental cell.

[39]  C. Deng,et al.  TGF-β/Smad3 Signals Repress Chondrocyte Hypertrophic Differentiation and Are Required for Maintaining Articular Cartilage , 2001, The Journal of cell biology.

[40]  K. Lyons,et al.  The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. , 2000, Development.

[41]  D. Ovchinnikov,et al.  Col2a1‐directed expression of Cre recombinase in differentiating chondrocytes in transgenic mice , 2000, Genesis.

[42]  E. Nishida,et al.  Involvement of the p38 Mitogen-activated Protein Kinase Pathway in Transforming Growth Factor-β-induced Gene Expression* , 1999, The Journal of Biological Chemistry.

[43]  A. McMahon,et al.  Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. , 1999, Genes & development.

[44]  K. Nakamura,et al.  p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. , 1999, Experimental cell research.

[45]  D. Kingsley,et al.  GDF5 coordinates bone and joint formation during digit development. , 1999, Developmental biology.

[46]  A. McMahon,et al.  Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. , 1998, Science.

[47]  F. Long,et al.  Regulation of growth region cartilage proliferation and differentiation by perichondrium. , 1998, Development.

[48]  K. Irie,et al.  TAK1 Mediates the Ceramide Signaling to Stress-activated Protein Kinase/c-Jun N-terminal Kinase* , 1997, The Journal of Biological Chemistry.

[49]  D. Kingsley,et al.  Joint patterning defects caused by single and double mutations in members of the bone morphogenetic protein (BMP) family. , 1996, Development.

[50]  B. Lanske,et al.  PTH/PTHrP Receptor in Early Development and Indian Hedgehog--Regulated Bone Growth , 1996, Science.

[51]  Clifford J. Tabin,et al.  Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein , 1996, Science.

[52]  K. Irie,et al.  A Novel Kinase Cascade Mediated by Mitogen-activated Protein Kinase Kinase 6 and MKK3* , 1996, The Journal of Biological Chemistry.

[53]  R. Sidman,et al.  Chondrodysplasia and neurological abnormalities in ATF-2-deficient mice , 1996, Nature.

[54]  K. Irie,et al.  Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction , 1995, Science.

[55]  V. Lefebvre,et al.  Use of a New Rat Chondrosarcoma Cell line to Delineate a 119-Base Pair Chondrocyte-specific Enhancer Element and to Define Active Promoter Segments in the Mouse Pro-α1(II) Collagen Gene (*) , 1995, The Journal of Biological Chemistry.

[56]  V. Lefebvre,et al.  Characterization of primary cultures of chondrocytes from type II collagen/beta-galactosidase transgenic mice. , 1994, Matrix biology : journal of the International Society for Matrix Biology.

[57]  E. Schwarz,et al.  Transforming growth factor-beta stimulates cyclin D1 expression through activation of beta-catenin signaling in chondrocytes. , 2006, The Journal of biological chemistry.

[58]  Xizhi Guo,et al.  Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. , 2004, Genes & development.

[59]  R. Derynck,et al.  Smad-dependent and Smad-independent pathways in TGF-beta family signalling. , 2003, Nature.