Our research on achondroplasia and other skeletal dysplasias

(See PubMed for a complete publication list)

Reviews

Krejci P. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med. 2019;381(13):1291.
Krejci P. (2014) The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate. Mutat Res Rev Mutat Res. 759:40-8.
Foldynova-Trantirkova S, Wilcox WR, Krejci P. (2012) Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat. 33:29-41.
Pejchalova K, Krejci P, Wilcox WR. (2007) C-natriuretic peptide: an important regulator of cartilage. Mol Genet Metab. 92:210-5.

Mechanisms of skeletal dysplasias

Bosakova M, Abraham SP, Nita A, Hruba E, Buchtova M, Taylor SP, Duran I, Martin J, Svozilova K, Barta T, Varecha M, Balek L, Kohoutek J, Radaszkiewicz T, Pusapati GV, Bryja V, Rush ET, Thiffault I, Nickerson DA, Bamshad MJ; University of Washington Center for Mendelian Genomics, Rohatgi R, Cohn DH, Krakow D, Krejci P. Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling. EMBO Mol Med. 2020;12(11):e11739.
Barad M, Csukasi F, Bosakova M, Martin JH, Zhang W, Paige Taylor S, Lachman RS, Zieba J, Bamshad M, Nickerson D, Chong JX, Cohn DH, Krejci P, Krakow D, Duran I. Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia. EBioMedicine. 2020;62:103075.
Kunova Bosakova M, Nita A, Gregor T, Varecha M, Gudernova I, Fafilek B, Barta T, Basheer N, Abraham SP, Balek L, Tomanova M, Fialova Kucerova J, Bosak J, Potesil D, Zieba J, Song J, Konik P, Park S, Duran I, Zdrahal Z, Smajs D, Jansen G, Fu Z, Ko HW, Hampl A, Trantirek L, Krakow D, Krejci P. Fibroblast growth factor receptor influences primary cilium length through an interaction with intestinal cell kinase. Proc Natl Acad Sci U S A. 2019;116(10):4316-4325.
Csukasi F, Duran I, Barad M, Barta T, Gudernova I, Trantirek L, Martin JH, Kuo CY, Woods J, Lee H, Cohn DH, Krejci P, Krakow D. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. Sci Transl Med. 2018;10(459):eaat9356.
Fafilek B, Balek L, Kunova Bosakova M, Varecha M, Nita A, Gregor T, Gudernova I, Krenova J, Ghosh S, Piskacek M, Jonatova L, Cernohorsky N, Zieba JT, Kostas M, Haugsten EM, Wesche J, Erneux C, Trantirek L, Krakow D, Krejci P. The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases to FGF-receptor. Science Signalling 2018;11(548).
Balek L, Nemec P , Konik P , Kunova Bosakova M, Varecha M, Gudernova I, Krakow D, Krejci P. Proteomic analyses of signalling complexes associated with receptor tyrosine kinase identify novel members of fibroblast growth factor receptor 3 interactome. Cellular Signaling 2018;42:144-154.
Kunova Bosakova M, Varecha M, Hampl M, Duran I, Buchtova M, Dosedelova H, Machat R, Xie Y, Ni Z, Martin JH, Chen L, Jansen G, Krakow D, Krejci P. Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Hum Mol Genet. 2018;27(6):1093-1105.
Kant SG, Cervenkova I, Balek L, Trantirek L, Santen GW, de Vries MC, van Duyvenvoorde HA, van der Wielen MJ, Verkerk AJ, Uitterlinden A, Hannema SE, Wit JM, Oostdijk W, Krejci P, Losekoot M. (2015) A novel variant of FGFR3 causes proportionate short stature. Eur J Endocrinol. 172:763-70.
Buchtova M, Oralova V, Aklian A, Masek J, Vesela I, Ouyang Z, Obadalova T, Konecna Z, Spoustova T, Pospisilova T, Matula P, Varecha M, Balek L, Gudernova I, Jelinkova I, Duran I, Cervenkova I, Murakami S, Kozubik A, Dvorak P, Bryja V, Krejci P. (2015) Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage. Biochim Biophys Acta. 1852:839-50.
Wang Y, Zhou X, Oberoi K, Phelps R, Couwenhoven R, Sun M, Rezza A, Holmes G, Percival CJ, Friedenthal J, Krejci P, Richtsmeier JT, Huso DL, Rendl M, Jabs EW. (2012) p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice. J Clin Invest. 122:2153-64.
Krejci P, Aklian A, Kaucka M, Sevcikova E, Prochazkova J, Masek J, Mikolka P, Pospisilova T, Spoustova T, Weis M, Paznekas W, Wolf J, Gutkind JS, Wilcox WR, Kozubik A, Wang Jabs E, Bryja V, Salazar L, Vesela I, Balek L. (2012) Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation. PLoS ONE. 7:e35826
Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N, Estrada KD, Lyons KM, Deixler H, Robinson H, Chitayat D, Curry CJ, Lachman RS, Wilcox WR, Krakow D. (2012) Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient Canonical FGF Signaling. Am J Hum Genet. 90:550-557.
Krejci P, Prochazkova J, Smutny J, Chlebova K, Lin P, Aklian A, Bryja V, Kozubik A, Wilcox WR. (2010) FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence. Bone. 47:102-10.
Krejci P, Salazar L, Kashiwada TA, Chlebova K, Salasova A, Thompson LM, Bryja V, Kozubik A, Wilcox WR. (2008) Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 3:e3961.
Krejci P, Prochazkova J, Bryja V, Jelinkova P, Pejchalova K, Kozubik A, Thompson LM, Wilcox WR. (2009) Fibroblast growth factor inhibits interferon gamma-STAT1 and interleukin 6-STAT3 signaling in chondrocytes. Cell Signal. 21:151-60.
Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bükülmez H, Balmes G, Krejci P, Mekikian PB, Otani K, Yamaura I, Warman ML, Givol D, Murakami S. (2009) FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet. 18:227-40.
Krejci P, Salazar L, Goodridge HS, Kashiwada TA, Schibler MJ, Jelinkova P, Thompson LM, Wilcox WR. (2008) STAT1 and STAT3 do not participate in FGF-mediated growth arrest in chondrocytes. J Cell Sci. 121:272-81.
Krejci P, Masri B, Salazar L, Farrington-Rock C, Prats H, Thompson LM, Wilcox WR. (2007) Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins. J Biol Chem. 282:2929-36.
Krejci P, Bryja V, Pachernik J, Hampl A., Pogue R, Mekikian P, Wilcox WR. (2004) FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS chondrocytes. Experimental Cell Research. 297: 152-164.

Drug development

Kimura T, Bosakova M, Nonaka Y, Hruba E, Yasuda K, Futakawa S, Kubota T, Fafilek B, Gregor T, Abraham SP, Gomolkova R, Belaskova S, Pesl M, Csukasi F, Duran I, Fujiwara M, Kavkova M, Zikmund T, Kaiser J, Buchtova M, Krakow D, Nakamura Y, Ozono K, Krejci P. An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice. Sci Transl Med. 2021;13(592):eaba4226.
Balek L, Buchtova M, Kunova Bosakova M, Varecha M, Foldynova-Trantirkova S, Gudernova I, Vesela I, Havlik J, Neburkova J, Turner S, Krzyscik MA, Zakrzewska M, Klimaschewski L, Claus P, Trantirek L, Cigler P, Krejci P. Nanodiamonds as "artificial proteins": Regulation of a cell signalling system using low nanomolar solutions of inorganic nanocrystals. Biomaterials 2018;176:106-121.
Fafilek B, Hampl M, Ricankova N, Vesela I, Balek L, Kunova Bosakova M, Gudernova I, Varecha M, Buchtova M, Krejci P. (2017) Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage 2017;25(9):1522-1530.
Balek L, Gudernova I, Vesela I, Hampl M, Oralova V, Kunova Bosakova M, Varecha M, Nemec P, Hall T, Abbadessa G, Hatch N, Buchtova M, Krejci P. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3. Bone 2017;105:57-66.
Gudernova I, Balek L, Varecha M, Kucerova Fialova J, Kunova Bosakova M, Fafilek B, Palusova V, Uldrijan S, Trantirek L, Krejci P. (2017) Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480. Oncotarget. 8:109319-109331.
Gudernova I, Foldynova-Trantirkova S, Ghannamova BE, Fafilek B, Varecha M, Balek L, Hruba E, Jonatova L, Jelinkova I, Kunova Bosakova M, Trantirek L, Mayer J, Krejci P. (2017) One reporter for in-cell activity profiling of majority of protein kinase oncogenes. Elife. 2017;6. pii: e21536
Gudernova I, Vesela I, Balek L, Buchtova M, Dosedelova H, Kunova M, Pivnicka J, Jelinkova I, Roubalova L, Kozubik A, Krejci P (2016). Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short- stature syndromes. Hum Mol Genet. 25(1):9-23.
Wendt DJ, Dvorak-Ewell M, Bullens S, Lorget F, Bell SM, Peng J, Castillo S, Aoyagi-Scharber M, O'Neill CA, Krejci P, Wilcox WR, Rimoin DL, Bunting S. (2015) Neutral endopeptidase-resistant C-type natriuretic Peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther. 353:132-49.
Scuto A, Krejci P, Popplewell L, Wu J, Wang Y, Kujawski M, Kowolik C, Xin H, Chen L, Wang Y, Kretzner L, Yu H, Wilcox WR, Yen Y, Forman S, Jove R. (2011) The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia. 25:538-50.
Krejci P, Murakami S, Prochazkova J, Trantirek L, Chlebova K, Ouyang Z, Aklian A, Smutny J, Bryja V, Kozubik A, Wilcox WR. (2010) NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells. J Biol Chem. 285: 20644-53.
Krejci P, Pejchalova K, Wilcox WR. (2007) Simple, mammalian cell-based assay for identification of inhibitors of the Erk MAP kinase pathway. Investigational New Drugs. 25: 391-395.
Krejci P, Masri B, Fontaine V, Mekikian PB, Weis M, Prats H, Wilcox WR. (2005) Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J Cell Sci. 118: 5089-5100.