The International CCN Society

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Karen M. Lyons

 

Karen M. Lyons, PhD
Department of Molecular, Cell & Developmental Biology
Department of Orthopaedic Surgery
University of California, Los Angeles
Room 410 615 Charles E Young Drive South
Los Angeles, CA 90095 USA
Tel: (310) 825-5480
klyons@mednet.ucla.edu

Present Position

  • Professor
    Department of Molecular, Cell & Developmental Biology
    Department of Orthopaedic Surgery
    University of California, Los Angeles

Societies

  • American Association for the Advancement of Science
  • American Society for Bone and Mineral Research
  • American Society for Matrix Biology
  • Orthopaedic Research Society
  • International CCN Society
  • American Association of Anatomists
  • American Society for Biochemistry and Molecular Biology

Awards

  • David Paul Kane Scholar (UCLA)
  • Dwyer Award for Excellence in Research, UCLA
  • Hospital for Special Surgery Distinguished Lecturer
  • AIMM (Advances in Mineral Metabolism) Investigator Award
  • Marta Marx Eradicate Scleroderma Award, The Scleroderma Foundation
  • Kappa Delta Ann Doner Vaughn Award, American Association of Orthopaedic Surgeons

Editorial Boards

  • Journal of Cell Communication and Signaling
  • Fibrosis and Tissue Repair 

Research Themes

  • Signaling Pathways Controlling Formation of the Growth Plate
    The growth plate is one of the few tissues in vertebrates in which cells are stratified according to their differentiation status. This makes it possible to use phenotypic analysis of mice to investigate the functions of genes in specific aspects of commitment, maintenance, proliferation, differentiation, and survival.
    Most skeletal elements develop through endochondral ossification, in which a condensation of mesenchymal cells forms, differentiates into chondrocytes, and eventually forms a growth plate. The growth plate contains chondrocytes that are stratified according to their differentiation status. The pericarticular cells are slowly proliferating and produce less cartilage-specific matrix than do more differentiated cells. The proliferating chondrocytes are rapidly dividing cells, and their planes of cell division are oriented such that they form columns of chondrocytes. This leads to elongation of the developing skeletal element. Cells are maintained in the proliferative phase by the action of PthrP, which is expressed in the periarticular cells but diffuses through the proliferative zone. Chondrocytes most distal to the source of PthrP are no longer under its influence, and therefore become post-mitotic. Once they do this, they start to express Indian Hedgehog. They also begin to terminally differentiate, marked by the onset of hypertrophy. IHH produced by the pre-hypertrophic chondrocytes diffuses back to the periarticular cells to maintain PthrP expression. This negative feedback loop maintains the length of the growth plate.
    Our laboratory is investigating how Bone Morphogenetic Proteins (BMPs) regulate growth plate formation and maintenance. We have found that BMP signaling is essential for the initial formation of chondrocyte condensations. Once a growth plate forms, we found that BMP signaling is essential for the induction of IHH. This induction appears to be direct and mediated by canonical BMP pathways. The ability of TGF-betas to promote chondrogenesis in vitro has been known for decades, but the roles of TGF-beta pathways in vivo in the growth plate remain poorly defined. We are investigating these roles in vivo by generating mice deficient in type I TGF-beta receptors and the TGF-beta Smads, Smads 2 and 3. Interestingly, in contrast to the BMPs, TGF-betas seem to exert their effects in chondrocytes primarily through non-canonical pathways. We are currently identifying these non-canonical pathways.
  • Functions of CCN proteins in vivo
    Functions of CCN proteins in skeletal tissues. Matricellular proteins have been defined as residing in the ECM, but having regulatory rather than structural roles. The CCN family of matricellular proteins includes connective tissue growth factor CCN1/Cyr61, CCN2/CTGF, CCN3/NOV, and CCN4/Wisp1. We are defining the functions of these CCN proteins in development and disease. For example, we found that CCN2 is essential for chondrogenesis. Mice lacking CCN2 exhibit profound chondrodysplasia and die immediately after birth. The chondrodysplasia is due in part to defective extracellular matrix production. In addition, expression of integrins that interact with the ECM is defective in Ccn2 mutants. Moreover, CCN2 itself is a ligand for integrins that are essential for cartilage function. We are currently examining other mechanisms of action of CCN2 and related CCN proteins in the growth plate. In addition, we have found that several other members of the CCN family are essential for the formation of cartilage and bone, and are currently investigating the mechanisms of CCN action in these tissues.
    Functions of CCN proteins in angiogenesis. In vitro studies have shown that CCN2/CTGF is a potent pro-angiogenic factor in vitro. Other in vitro studies have demonstrated ant-angiogenic properties. Using global and conditional mutant alleles of Ccn2, we find evidence that CCN2 is required for angiogenesis. For example, loss of CCN2 in the growth plate impairs VEGF expression and therefore, vascular invasion of the growth plate is defective. More recently, we have identified a direct role of CCN2 in endothelial cells. Loss in these cells leads to defective vascular remodeling. We are currently exploring the mechanisms by which CCN2 mediates this remodeling and pericyte recruitment. We are also investigating shared and unique functions of CCN2 and other CCN family members in angiogenesis.

Selected Recent Publications

  • Suwanwela J, Farber CR, Haung BL, Song B, Pan C, Lyons KM, Lusis AJ.
    Systems genetic analysis of mouse chondrocyte differentiation
    J Bone Miner Res. 2010 Oct 15. [Epub ahead of print].
  • Huang, B.L., Brugger, S.M. and Lyons, KM.
    Stage-specific control of connective tissue growth factor (CTGF/CCN2) expression in chondrocytes by sox9 and β-catenin.
    J. Biol. Chem. (2010) 285: 27702-12.
  • Ohyama T, Basch ML, Mishina Y, Lyons KM, Segil N, Groves AK.
    BMP signaling is necessary for patterning the sensory and nonsensory regions of the developing mammalian cochlea.
    J Neurosci. 2010 Nov 10;30(45):15044-51.
  • Nishida T, Emura K, Kubota S, Lyons KM, Takigawa M.
    CCN family 2/connective tissue growth factor (CCN2/CTGF) promotes osteoclastogenesis via induction of and interaction with dendritic cell-specific transmembrane protein (DC-STAMP).
    J Bone Miner Res. 2010 Aug 18. [Epub ahead of print]
  • Stevens JR, Miranda-Carboni GA, Singer MA, Brugger SM, Lyons KM, Lane TF.
    Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells.
    J Bone Miner Res. 2010 Oct;25(10):2138-47.
  • Edson MA, Nalam RL, Clementi C, Franco HL, Demayo FJ, Lyons KM, Pangas SA, Matzuk MM.
    Granulosa cell-expressed BMPR1A and BMPR1B have unique functions in regulating fertility but act redundantly to suppress ovarian tumor development.
    Mol Endocrinol. 2010 Jun;24(6):1251-66.
  • Retting, KN, Song, B, and Lyons, KM.
    BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation.
    Development 2009 136: 1093-104.
  • Maeda A, Nishida T, Aoyama E, Kubota S, Lyons KM, Kuboki T, Takigawa M.
    CCN family 2/connective tissue growth factor modulates BMP signaling as a signal conductor, which action regulates the proliferation and differentiation of chondrocytes.
    J. Biochem. 2009 145: 207-16.
  • Nishida T, Kondo S, Maeda A, Kubota S, Lyons KM, Takigawa M.
    CCN family 2/connective tissue growth factor (CCN2/CTGF) regulates the expression of Vegf through Hif-1alpha expression in a chondrocytic cell line, HCS-2/8, under hypoxic condition
    Bone 2009, 44:24-31.
  • Crawford LA, Guney MA, Oh YA, Deyoung RA, Valenzuela DM, Murphy AJ, Yancopoulos GD, Lyons KM, Brigstock DR, Economides A, Gannon M.
    Connective tissue growth factor (CTGF) inactivation leads to defects in islet cell lineage allocation and beta-cell proliferation.
    Mol Endo. 2009. 23: 324-6.
  • Kuiper, EJ, van Zijderveld R, Rosetenberg, P, Lyons, KM, Godschmeding, R, Klaassen, I, Van Noordern CJ, Schlingemann, RO.
    Connective tissue growth factor is necessary for retinal capillary Basal lamina thickening in diabetic mice.
    J Histochem Cytochem. 2008. 56:785-92.
  • Sengle G, Ono RN, Lyons KM, Bächinger HP, Sakai LY.
    A new model for growth factor activation: type II receptors compete with the prodomain of BMP-7.
    Mol Biol 2008. 38: 1025-39.
  • Pala D, Kapoor M, Woods A, Kennedy L, Liu S, Chen S, Bursell L, Lyons KM, Carter DE, Beier F, Leask A.
    Focal adhesion kinase/Src suppresses early chondrogenesis: central role of CCN2.
    J Biol Chem. 2008. 283(14):9239-47.
  • Huang, B-L, Dornbach, L.M., and Lyons, K.M.
    The 5' untranslated regions (UTRs) of CCN1, CCN2, and CCN4 exhibit cryptic promoter activity.
    J. Cell. Commun. & Sign. 2008. 1: 17--32.
  • Nihsida, T., Kawaki, H., Baxter, R., DeYoung, R.A., and Lyons, K.M.
    CCN2 (Connective Tissue Growth Factor)is essential for extracellular matrix production and integrin signaling in chondrocytes.
    J. Cell. Commun. & Signal. 2007. 1: 45-58.
  • Kennedy L, Liu S, Shi-Wen X, Chen Y, Eastwood M, Sabetkar M, Carter DE, Lyons KM, Black CM, Abraham DJ, Leask A.
    CCN2 is necessary for the function of mouse embryonic fibroblasts.
    Exp. Cell Res. 2007. 313:952-64.
  • Gamradt SC, Abe N, Bahamonde ME, Lee YP, Nelson SD, Lyons KM, Lieberman JR.
    Tracking Expression of Virally Mediated BMP-2
    in Gene Therapy for Bone Repair.
    Clin Orthop Relat Res. 2006. 450: 238-45.
  • Shi-wen X, Stanton LA, Kennedy L, Pala D, Chen Y, Howat SL, Renzoni EA, Carter DE, Bou-Gharios G, Stratton RJ, Pearson JD, Beier F, Lyons KM, Black CM, Abraham DJ, Leask A.
    CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts.
    J Biol Chem. 2006. 281: 10715-26.
  • Wan DC, Shi YY, Nacamuli RP, Quarto N, Lyons KM, Longaker MT.
    Osteogenic differentiation of mouse adipose-derived adult stromal cells requires retinoic acid and bone morphogenetic protein receptor type IB signaling.
    PNAS (USA) 2006. 103: 12335-40.
  • Kim, J. Wu, H.H., Lander, A.D., Lyons, K.M., Matzuk M.M. and Caloff, A.
    GDF11 controls the timing of progenitor cell competence in developing retina.
    Science. 2005. 308: 1927-30.
  • Zakin, L., Reversade, B., Kuroda, H., Lyons, K.M., and DeRobertis, E.M.
    Sirenomelia in Bmp7 and Tsg compound mutant mice: requirement for BMP signaling in the development of the posterior ventral mesoderm.
    Development 2005. 132: 2489-99.
  • Yoon, B.S., Ovchinnikov, D.A., Yoshii, I., Mishina, Y., Behringer, R.R., and Lyons, K.M.
    The type I BMP receptors Bmpr1a and Bmpr1b have overlapping functions and are essential for early chondrogenesis in vivo.
    PNAS (USA) 2005. 102: 5062-7.
  • Lee, N.V., Rodrigues-Manzaneque J.C., Thai, S.N., Twal, W.O., Luque, A., Lyons, K.M., Argraves, W.S. and Iruele-Arispe, M.L.
    Fibulin-1 acts as a cofactor for the matrix metalloprotease ADAMTS-1.
    J. Biol. Chem. 2005 Aug. 1 [Epub ahead of print]
  • Kobayashi T, Lyons KM, McMahon AP, Kronenberg HM.
    BMP signaling stimulates cellular differentiation at multiple steps during cartilage development.
    PNAS (USA) 2005. 102:18023-7
  • Andl, T, Ahn, K, Kairo, A, Croft, NJ, Cebra-Thomas, JA., Lyons, KM, Mishina, Y, Crenshaw III, EB, and Millar, SE.
    Epithelial BmprIa regulates proliferation and differentiation in postnatal hair follicles and is essential for tooth development.
    Development. 2004. 131: 2257-68.
  • Chuva De Sousa Lopes SM, Feijen A, Korving J, Korchynskyi O, Larsson J, Karlsson S, Ten Dijke P, Lyons KM, Goldschmeding R, Doevendans P, Mummery C.
    Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction.
    Dev Dyn. 2004. 231: 542-50.
  • Chen, Y., Abraham, D.J., Shi-Wen, X., Black, C.M., Lyons, K.M., and Leask, A.
    CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin.
    Mol. Biol. Cell. 2004. 15: 5635-46.
  • Brugger, S.M., Merrill, A.E., Torres-Vasquez, J., Wu, N., Ting, M-C., Cho, J.Y-M., Dobias, S.L., Yi, S.E., Lyons,, K., Bell, J.R., Arora, K., Warrior, R., and Maxson, R.
    A phylogenetically conserved cis-regulatory module in the Msx2 promoter is sufficient for BMP-dependent transcription in murine and Drosophila embryos.
    Development 2004. 131, 5153-65.
  • Yoon, B.S., and Lyons, K.M.
    Multiple functions of BMPs in chondrogenesis.
    J Cell Biochem. 2004. 93:93-103.
  • Delot, E., Bahamonde, M.E., Zhao, M., and Lyons, KM.
    BMP signaling is required for septation of the mammalian outflow tract.
    Development. 2004. 130: 209-220.
  • Wu, H-H., Ivkovic, S., Murray, R.C., Jaramillo, S., Lyons, K.M., Johnson, J.E., and Calof, A.L.
    Autoregulation of Neurogenesis by GDF11.
    Neuron. 2003. 37: 1-10.
  • Ivkovic, S., Yoon, B., Popoff, SN, Safadi, FF, Libuda, DE, Stephenson, RC, Daluisky, A. and Lyons, K.M.
    Connective tissue growth factor is required for chondrogenesis and growth plate angiogenesis.
    Development. 2003. 130: 2779-2791.
  • Nishimura, I., Drake, T.A., Lusis, A.J., Lyons, K.M., Nadeau, J.H., and Zernik, J.
    ENU Mutagenesis and quantitative trait loci (QTL) analysis in mice: novel technologies for searching polygenic determinants of craniofacial abnormalities.
    Crit,. Rev. Oral Biol. Med. 2003. 14:320-30.
  • Daluiski, A., Engstrand, T., Bahamande, M.E., Gamer, L.A., Cox, K., Stevenson, S., Rosen, V., and Lyons, K.M.
    BMP3 is a negative regulator of bone density.
    Nature Genet. 2001. 27: 84-88.
  • Yi, S.E., Lu, JH., Chen, J., Yoon, B.S., LaPolt, P., and Lyons, K.M.
    The type I BMP receptor BmprIB is essential for female reproductive function.
    PNAS (USA) 2001. 98: 7994-7999.