BACKGROUND: Achondroplasia (ACH) is one of the most prevalent genetic forms of short-limbed skeletal dysplasia, caused by gain-of-function mutations in the receptor tyrosine kinase FGFR3. In August 2021, the C-type natriuretic peptide (CNP) analog vosoritide was approved for the treatment of ACH. A total of six other inhibitors of FGFR3 signaling are currently undergoing clinical evaluation for ACH. This progress creates an opportunity for children with ACH, who may gain early access to the treatment by entering clinical trials before the closure of their epiphyseal growth plates and cessation of growth. Pathophysiology associated with the ACH, however, demands a long observational period before admission to the interventional trial. Public patient registries can facilitate the process by identification of patients suitable for treatment and collecting the data necessary for the trial entry. RESULTS: In 2015, we established the prospective ACH registry in the Czechia and the Slovak Republic ( http://www.achondroplasia-registry.cz ). Patient data is collected through pediatric practitioners and other relevant specialists. After informed consent is given, the data is entered to the online TrialDB system and stored in the Oracle 9i database. The initial cohort included 51 ACH children (average age 8.5 years, range 3 months to 14 years). The frequency of selected neurological, orthopedic, or ORL diagnoses is also recorded. In 2015-2021, a total of 89 measurements of heights, weights, and other parameters were collected. The individual average growth rate was calculated and showed values without exception in the lower decile for the appropriate age. Evidence of paternal age effect was found, with 58.7% of ACH fathers older than the general average paternal age and 43.5% of fathers older by two or more years. One ACH patient had orthopedic limb extension and one patient received growth hormone therapy. Low blood pressure or renal impairment were not found in any patient. CONCLUSION: The registry collected the clinical information of 51 pediatric ACH patients during its 6 years of existence, corresponding to ~ 60% of ACH patients living in the Czechia and Slovak Republic. The registry continues to collect ACH patient data with annual frequency to monitor the growth and other parameters in preparation for future therapy.

• Klíčová slova
• Achondroplasia, FGFR3, ReACH, Registry, Skeletal dysplasia, Treatment,
• MeSH
• achondroplazie * epidemiologie   genetika   MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mutace MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   MeSH
• registrace MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Slovenská republika MeSH
• Názvy látek
• receptor fibroblastových růstových faktorů, typ 3 MeSH

Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics.

• MeSH
• achondroplazie genetika   patofyziologie   MeSH
• buňky NIH 3T3 MeSH
• chondrocyty metabolismus   MeSH
• chrupavka metabolismus   MeSH
• cilie patologie   fyziologie   MeSH
• ciliopatie genetika   patofyziologie   MeSH
• fenotyp MeSH
• fibroblastové růstové faktory metabolismus   MeSH
• lidé MeSH
• myši MeSH
• primární buněčná kultura MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   metabolismus   MeSH
• růstová ploténka metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• thanatoforní dysplazie genetika   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• FGFR3 protein, human MeSH Prohlížeč
• fibroblastové růstové faktory MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH

In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for the common genetic form of dwarfism in humans, achondroplasia (ACH). Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia [HCH], ACH, thanatophoric dysplasia [TD]), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans), and cancer (multiple myeloma [MM], prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer.

• MeSH
• chondrocyty metabolismus   patologie   MeSH
• chrupavka abnormality   metabolismus   MeSH
• fibroblastové růstové faktory genetika   metabolismus   MeSH
• fosfatidylinositol-3-kinasy genetika   metabolismus   MeSH
• kosti a kostní tkáň abnormality   metabolismus   MeSH
• kůže metabolismus   patologie   MeSH
• letální geny MeSH
• lidé MeSH
• MAP kinasový signální systém genetika   MeSH
• mezibuněčná komunikace MeSH
• mutace MeSH
• nádory kůže genetika   metabolismus   patologie   MeSH
• natriuretický peptid typu C genetika   metabolismus   MeSH
• osteochondrodysplazie genetika   metabolismus   patologie   MeSH
• proliferace buněk MeSH
• receptor fibroblastových růstových faktorů, typ 3 * genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• FGFR3 protein, human MeSH Prohlížeč
• fibroblastové růstové faktory MeSH
• fosfatidylinositol-3-kinasy MeSH
• natriuretický peptid typu C MeSH
• receptor fibroblastových růstových faktorů, typ 3 * MeSH
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

Oncogenic activation of the RAS-ERK MAP kinase signaling pathway can lead to uncontrolled proliferation but can also result in apoptosis or premature cellular senescence, both regarded as natural protective barriers to cell immortalization and transformation. In FGFR3-related skeletal dyplasias, oncogenic mutations in the FGFR3 receptor tyrosine kinase cause profound inhibition of cartilage growth resulting in severe dwarfism, although many of the precise mechanisms of FGFR3 action remain unclear. Mutated FGFR3 induces constitutive activation of the ERK pathway in chondrocytes and, remarkably, can also cause both increased proliferation and apoptosis in growing cartilage, depending on the gestational age. Here, we demonstrate that FGFR3 signaling is also capable of inducing premature senescence in chondrocytes, manifested as reversible, ERK-dependent growth arrest accompanied by alteration of cellular shape, loss of the extracellular matrix, upregulation of senescence markers (alpha-GLUCOSIDASE, FIBRONECTIN, CAVEOLIN 1, LAMIN A, SM22alpha and TIMP 1), and induction of senescence-associated beta-GALACTOSIDASE activity. Our data support a model whereby FGFR3 signaling inhibits cartilage growth via exploiting cellular responses originally designed to eliminate cells harboring activated oncogenes.

• MeSH
• apoptóza MeSH
• chondrocyty enzymologie   patologie   MeSH
• extracelulární matrix metabolismus   MeSH
• extracelulárním signálem regulované MAP kinasy metabolismus   MeSH
• fenotyp MeSH
• krysa rodu Rattus MeSH
• onkogeny genetika   MeSH
• proliferace buněk MeSH
• receptor fibroblastových růstových faktorů, typ 3 metabolismus   MeSH
• signální transdukce * MeSH
• stárnutí buněk * MeSH
• tvar buňky MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• extracelulárním signálem regulované MAP kinasy MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH

Activation of fibroblast growth factor receptor 3 (FGFR3) leads to attenuation of cartilage growth. The members of the STAT family of transcription factors are believed to participate in FGFR3 signaling in cartilage, however the molecular mechanism of this action is poorly understood. Here, we demonstrate that a chronic FGF stimulus leads to accumulation of STAT1, 3, 5 and 6, evident in both in vitro chondrocyte model and murine limb explant cultures. Despite the accumulation, both endogenous and cytokine-induced activation of STAT1 and STAT3 is impaired by FGF, as demonstrated by imaging of active STAT nuclear translocation and analyses of STAT activatory phosphorylation and transcriptional activation. Further, we demonstrate that FGF induces expression of CIS, SOCS1 and SOCS3 inhibitors of gp130, a common receptor for the IL6-family of cytokines. Since cytokine-gp130 signaling represents an important positive regulator of cartilage, its inhibition may contribute to the growth-inhibitory effect of FGFR3 in cartilage.

• MeSH
• chondrocyty účinky léků   metabolismus   MeSH
• cytokinový receptor gp130 metabolismus   MeSH
• fibroblastový růstový faktor 2 farmakologie   MeSH
• interferon gama antagonisté a inhibitory   farmakologie   MeSH
• interleukin-6 antagonisté a inhibitory   farmakologie   MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• protein SOCS1 MeSH
• protein SOCS3 MeSH
• proteiny SOCS metabolismus   MeSH
• receptor fibroblastových růstových faktorů, typ 3 metabolismus   MeSH
• sekvence nukleotidů MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 antagonisté a inhibitory   metabolismus   MeSH
• transkripční faktor STAT3 antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• cytokine inducible SH2-containing protein MeSH Prohlížeč
• cytokinový receptor gp130 MeSH
• fibroblastový růstový faktor 2 MeSH
• interferon gama MeSH
• interleukin-6 MeSH
• protein SOCS1 MeSH
• protein SOCS3 MeSH
• proteiny SOCS MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• Socs1 protein, mouse MeSH Prohlížeč
• Socs3 protein, mouse MeSH Prohlížeč
• transkripční faktor STAT1 MeSH
• transkripční faktor STAT3 MeSH

Activating mutations in FGFR3 tyrosine kinase cause several forms of human skeletal dysplasia. Although the mechanisms of FGFR3 action in cartilage are not completely understood, it is believed that the STAT1 transcription factor plays a central role in pathogenic FGFR3 signaling. Here, we analyzed STAT1 activation by the N540K, G380R, R248C, Y373C, K650M and K650E-FGFR3 mutants associated with skeletal dysplasias. In a cell-free kinase assay, only K650M and K650E-FGFR3 caused activatory STAT1(Y701) phosphorylation. Similarly, in RCS chondrocytes, HeLa, and 293T cellular environments, only K650M and K650E-FGFR3 caused strong STAT1 activation. Other FGFR3 mutants caused weak (HeLa) or no activation (293T and RCS). This contrasted with ERK MAP kinase activation, which was strongly induced by all six mutants and correlated with the inhibition of proliferation in RCS chondrocytes. Thus the ability to activate STAT1 appears restricted to the K650M and K650E-FGFR3 mutants, which however account for only a small minority of the FGFR3-related skeletal dysplasia cases. Other pathways such as ERK should therefore be considered as central to pathological FGFR3 signaling in cartilage.

• MeSH
• bezbuněčný systém metabolismus   MeSH
• biologické modely MeSH
• CHO buňky MeSH
• chrupavka metabolismus   MeSH
• Cricetulus MeSH
• extracelulárním signálem regulované MAP kinasy metabolismus   MeSH
• fosforylace MeSH
• HeLa buňky MeSH
• kosti a kostní tkáň patologie   MeSH
• křečci praví MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• mutantní proteiny fyziologie   MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   fyziologie   MeSH
• signální transdukce genetika   fyziologie   MeSH
• transkripční faktor STAT1 analýza   metabolismus   fyziologie   MeSH
• vývojové onemocnění kostí genetika   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• extracelulárním signálem regulované MAP kinasy MeSH
• mutantní proteiny MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• transkripční faktor STAT1 MeSH