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Human FGFR3 protein structure and FGFR3 signal transduction. Positions of the representative pathogenic variants in the FGFR3 gene are indicated. Ig, immunoglobulin-like domain; TM, transmembrane domain; TK, tyrosine kinase domain; STAT, signal transducer and activator of transcription; MAPK, mitogen activated protein kinase.
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Skeletal dysplasia is a diverse group of disorders that affect bone development and morphology. Currently, approximately 461 different genetic skeletal disorders have been identified, with over 430 causative genes. Among these, fibroblast growth factor receptor 3 ( FGFR3 )-related skeletal dysplasia is a relatively common subgroup of skeletal dyspl...
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... an extracellular ligand-binding domain, a transmembrane domain, and 2 intracellular tyrosine kinase domains. 8) Binding of various FGFs to FGFR3 induces receptor dimerization and transphosphorylation of tyrosine residues, 9) leading to activation of several downstream signaling pathways, including mitogen-activated protein kinase (MAPK) cascades (Fig. 1). 10,11) Gain-of-function variants in the FGFR3 gene lead to increased signal transduction of FGFR3, thus suppressing chondrocyte proliferation and differentiation. 12) This impairs endochondral ossification of long bones, leading to poor extension of the long bones. Loss of FGFR3 function induces overgrowth of long bones in mice with ...
Citations
... Germline mutations in FGFR 1-3 cause at least 20 congenital skeletal disorders [37], with achondroplasia, caused by activating (gain-of-function) mutations in FGFR3 resulting in constitutive activation of the MAPK pathway in chondrocytes which leads to inhibition of endochondral ossification [2,3]. Interestingly, patients with achondroplasia have been treated with recombinant human growth hormone (GH), a key regulator of IGF-I production [26][27][28] and although GH-induced production of IGF-I is believed to be a key mechanism for increasing growth velocity, final height remains suboptimal [31,[38][39][40]. A potential mechanism for the positive effects of IGF-I was demonstrated in an immortalized mouse chondrocyte cell line model for achondroplasia where IGF-1 prevented constitutively activated FGFR3-mediated apoptosis [31]. ...
... A potential mechanism for the positive effects of IGF-I was demonstrated in an immortalized mouse chondrocyte cell line model for achondroplasia where IGF-1 prevented constitutively activated FGFR3-mediated apoptosis [31]. However, enhanced GH-induced IGF-I production itself does not appear to be sufficient to override the inhibitory osteogenic effects of activated FGFR-3, and a number of other therapeutics are currently under study [38][39][40]. Indeed, several FGFR inhibitors have been evaluated in vitro and in achondroplasia mouse models with variable results and toxicities [41][42][43]. ...
Fibroblast growth factors and their receptors (FGFR) have major roles in both human growth and oncogenesis. In adults, therapeutic FGFR inhibitors have been successful against tumors that carry somatic FGFR mutations. In pediatric patients, trials testing these anti-tumor FGFR inhibitor therapeutics are underway, with several recent reports suggesting modest positive responses. Herein, we report an unforeseen outcome in a pre-pubescent child with an FGFR1-mutated glioma who was successfully treated with FDA-approved erdafitinib, a pan-FGFR inhibitor approved for treatment of Bladder tumors. While on treatment with erdafitinib, the patient experienced rapid skeletal and long bone overgrowth resulting in kyphoscoliosis, reminiscent of patients with congenital loss-of-function FGFR3 mutations. We utilized normal dermal fibroblast cells established from the patient as a surrogate model to demonstrate that insulin-like growth factor 1 (IGF-1), a factor important for developmental growth of bones and tissues, can activate the PI3K/AKT pathway in erdafitinib-treated cells but not the MAPK/ERK pathway. The IGF-I-activated PI3K/AKT signaling rescued normal fibroblasts from the cytotoxic effects of erdafitinib by promoting cell survival. We, therefore, postulate that IGF-I-activated P13K/AKT signaling likely continues to promote bone elongation in the growing child, but not in adults, treated with therapeutic pan-FGFR inhibitors. Importantly, since activated MAPK signaling counters bone elongation, we further postulate that prolonged blockage of the MAPK pathway with pan-FGFR inhibitors, together with actions of growth-promoting factors including IGF-1, could explain the abnormal skeletal and axial growth suffered by our pre-pubertal patient during systemic therapeutic use of pan-FGFR inhibitors. Further studies to find more targeted, and/or appropriate dosing, of pan-FGFR inhibitor therapeutics for children are essential to avoid unexpected off-target effects as was observed in our young patient.
... The phenotypes related to the FGFR3 gene include ACH, a common skeletal dysplasia causing short stature, thanatophoric dysplasia, which is a lethal skeletal dysplasia and CATSHL syndrome in which there is tall stature along with camptodactyly, scoliosis, and hearing loss. [8] In the SADDAN phenotype, there is severe ACH, along with developmental delay and acanthosis nigricans, and early respiratory failure leads to mortality. Thus, thanatophoric dysplasia, ACH, and hypochondroplasia (HCH) are all the result of pathogenic variants in the FGFR3. ...
Short stature may often be due to skeletal dysplasias affecting the limbs, spine, or both. A careful clinical evaluation will help in identifying the rhizomelic and mesomelic shortening of the limbs and scoliosis. The mutations in different genes involved in various pathways in skeletal development lead to phenotypes that present from infancy to childhood or adulthood. A systematic clinical evaluation with identification of the limb bowing or deformity, dysmorphic features, radiological findings from skull to toes, and a single gene or multi-gene panel testing will help in making an appropriate diagnosis. The clinical clues to skeletal dysplasia include skeletal disproportion, unexplained limb bowing, recurrent fractures, facial dysmorphism including flat facies and blue sclera in severe cases, and sometimes typical digital or cardiac abnormalities. The following review focuses on the postnatal presentation of skeletal dysplasias mostly referred for evaluation of short stature.
... A large number of DEGs that play essential roles in the regulation of bone development were identified. Key candidate genes were further identified through a combination of functional analysis with literature mining, including NKX3.2 [34][35][36][37][38][39][40], WLS [41][42][43], GREM1 [44][45][46], FGFR3 [47][48][49][50][51], HHEX [52][53][54], COL11A1 [55][56][57], and WNT16 [58,59]. These genes were mainly enriched in the BMP, FGF, Wnt, and Notch signaling pathways, suggesting that they are involved in the development of the pig vertebral column. ...
... A study on postmenopausal osteoporosis mice showed that FGFR3 activation inhibited the ability of bone regeneration and bone mineralization [50]. Human FGFR3-related skeletal dysplasia was also summarized in a recent review [51]. In the present study, FGFR3 showed a significantly lower expression in the 4-month-old pigs than in the 1-month-old ones ( Figure 4A), which is consistent with that reported above. ...
The porcine body length trait is an essential factor affecting meat production and reproductive performance. It is evident that the development/lengthening of individual vertebrae is one of the main reasons for increases in body length; however, the underlying molecular mechanism remains unclear. In this study, RNA-seq analysis was used to profile the transcriptome (lncRNA, mRNA, and miRNA) of the thoracic intervertebral cartilage (TIC) at two time points (1 and 4 months) during vertebral column development in Yorkshire (Y) and Wuzhishan pigs (W). There were four groups: 1- (Y1) and 4-month-old (Y4) Yorkshire pigs and 1- (W1) and 4-month-old (W4) Wuzhishan pigs. In total, 161, 275, 86, and 126 differentially expressed (DE) lncRNAs, 1478, 2643, 404, and 750 DE genes (DEGs), and 74,51, 34, and 23 DE miRNAs (DE miRNAs) were identified in the Y4 vs. Y1, W4 vs. W1, Y4 vs. W4, and Y1 vs. W1 comparisons, respectively. Functional analysis of these DE transcripts (DETs) demonstrated that they had participated in various biological processes, such as cellular component organization or biogenesis, the developmental process, the metabolic process, bone development, and cartilage development. The crucial bone development-related candidate genes NK3 Homeobox 2 (NKX3.2), Wnt ligand secretion mediator (WLS), gremlin 1 (GREM1), fibroblast growth factor receptor 3 (FGFR3), hematopoietically expressed homeobox (HHEX), (collagen type XI alpha 1 chain (COL11A1), and Wnt Family Member 16 (WNT16)) were further identified by functional analysis. Moreover, lncRNA, miRNA, and gene interaction networks were constructed; a total of 55 lncRNAs, 6 miRNAs, and 7 genes formed lncRNA–gene, miRNA–gene, and lncRNA–miRNA–gene pairs, respectively. The aim was to demonstrate that coding and non-coding genes may co-regulate porcine spine development through interaction networks. NKX3.2 was identified as being specifically expressed in cartilage tissues, and it delayed chondrocyte differentiation. miRNA-326 regulated chondrocyte differentiation by targeting NKX3.2. The present study provides the first non-coding RNA and gene expression profiles in the porcine TIC, constructs the lncRNA–miRNA–gene interaction networks, and confirms the function of NKX3.2 in vertebral column development. These findings contribute to the understanding of the potential molecular mechanisms regulating pig vertebral column development. They expand our knowledge about the differences in body length between different pig species and provide a foundation for future studies.
... Recently, several genes involved in the endochondral ossification process and their frequency in ISS conditions have been identified. Furthermore, several reports have demonstrated that mutations in the same genes, such as SHOX, natriuretic peptide receptor B (NPR2), aggrecan (ACAN), and fibroblast growth factor receptor 3 (FGFR3) can cause a wide spectrum of phenotypic abnormalities, ranging from skeletal dysplasia to ISS [13,14]. ...
... Individuals with monoallelic mutation of NPPC were reported with short stature with a tendency towards the development of small hands [25]. CNP analogues are the first approved precision medicine to enhance bone growth in achondroplasia caused by gain-of-function mutations in FGFR3 [14]. FGF signaling acts through FGFR3 which negatively regulates growth plate chondrogenesis [14]. ...
... CNP analogues are the first approved precision medicine to enhance bone growth in achondroplasia caused by gain-of-function mutations in FGFR3 [14]. FGF signaling acts through FGFR3 which negatively regulates growth plate chondrogenesis [14]. The clinical phenotypes of gain-of-function mutations in FGFR3 include thanatophoric dysplasia, achondroplasia, and hypochondroplasia [14]. ...
Children with short stature are often presented to pediatric endocrinologists. Short stature is defined as the height that is more than two standard deviations below the corresponding mean height for a specific age and sex in a reference population. Endocrine dysfunctions, including growth hormone deficiency/insensitivity, hypothyroidism, cortisol excess, precocious puberty, chronic disease (renal disease, diabetes mellitus, or inflammatory disease), and genetic disorders, should be assessed in patients presenting with short stature. In addition to medical history, physical examination, endocrine study, skeletal survey, and genetic testing are important for identifying the cause of short stature. Based on the next-generation sequencing analysis in patients with short stature, different genes that are unrelated to syndromic or non-syndromic short stature were identified. In particular, the genetic causes of short stature disrupting the growth plates and the pituitary-insulin-like growth factor axis have expanded. In recent years, the molecular level of chondrogenesis in the growth plates, including paracrine signals, extracellular matrix, and fundamental intracellular signals, has been reported. Moreover, new insights into the molecular pathogenesis of short stature are emerging. This article aimed to review the genetic causes of primary growth impairment in idiopathic short stature conditions.
Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including the most common form of human dwarfism, achondroplasia (ACH). Targeting FGFR3 activity holds great promise as a therapeutic approach for treatment of these diseases. Here, we established a receptor/adaptor translocation assay system that can specifically monitor FGFR3 activation, and we applied it to identify FGFR3 modulators from complex natural mixtures. An FGFR3-suppressing plant extract of Amaranthus viridis was identified from the screen, and two bioactive porphyrins, pheophorbide a (Pa) and pyropheophorbide a (PyroPa) were sequentially isolated from the extract and functionally characterized. Further analysis showed that Pa reduced excessive FGFR3 signaling by decreasing its half-life in FGFR3-overactivated multiple myeloma (MM) cells and chondrocytes. In an ex vivo culture system, Pa alleviated defective long bone growth in humanized ACH mice (FGFR3ACH mice). Overall, our study presents a novel approach to discovery and validation of plant extracts or drug candidates that target FGFR3 activation. The compounds identified by this approach may have potential applications as therapeutics for FGFR3-associated cancers and skeletal dysplasias.
Long bone growth is a fundamental determinant of final height. Growth, metabolism, and differentiation of chondrocytes, which are the key cellular players in this process, are regulated by systemic hormones, local factors, and cellular signaling pathways. This review provides an overview of the structural aspects of the growth plate, factors influencing chondrocyte function, and their impact on longitudinal bone growth. Systemic factors, including growth hormone, sex hormones, thyroid hormone, glucocorticoids, leptin, and insulin significantly affect chondrocyte proliferation and hypertrophy. Local factors, including transcription factors such as SRY-box 9 protein (SOX9), Runt-related transcription factor 2 (RUNX2), and bone morphogenetic proteins (BMPs), along with signaling pathways such as the Wnt pathway, play critical roles in chondrocyte proliferation and differentiation. These factors regulate gene expression, cell differentiation, and extracellular matrix synthesis. Additionally, Indian hedgehog (Ihh) and C-type natriuretic peptide (CNP) are involved in the complex signaling network governing chondrocyte function. Understanding molecular mechanisms underlying normal growth plate function has provided valuable insights into the genetic defects that impact growth and foundation for the development of effective therapeutic strategies for individuals with growth disorders.
