bone elongation
Recently Published Documents


TOTAL DOCUMENTS

41
(FIVE YEARS 14)

H-INDEX

12
(FIVE YEARS 1)

Author(s):  
Allison L. Machnicki ◽  
Cassaundra A. White ◽  
Chad A. Meadows ◽  
Darby McCloud ◽  
Sarah Evans ◽  
...  

Nearly one-third of children in the United States are overweight or obese by their pre-teens. Tall stature and accelerated bone elongation are characteristic features of childhood obesity, which co-occur with conditions such as limb bowing, slipped epiphyses, and fractures. Obese children paradoxically have normal circulating IGF-I, the major growth-stimulating hormone. Here we describe and validate a mouse model of excess dietary fat to examine mechanisms of growth acceleration in obesity. We used in vivo multiphoton imaging and immunostaining to test the hypothesis that high-fat diet increases IGF-I activity and alters growth plate structure before the onset of obesity. We tracked bone and body growth in male and female C57BL/6 mice (N = 114) on high-fat (60% kcal fat) or control (10% kcal fat) diets from weaning (3-weeks) to skeletal maturity (12-weeks). Tibial and tail elongation rates increased after brief (1-2 week) high-fat diet exposure without altering serum IGF-I. Femoral bone density and growth plate size were increased, but growth plates were disorganized in not-yet-obese high-fat diet mice. Multiphoton imaging revealed more IGF-I in the vasculature surrounding growth plates of high-fat diet mice, and increased uptake when vascular levels peaked. High-fat diet growth plates had more activated IGF-I receptors and fewer inhibitory binding proteins, suggesting increased IGF-I bioavailability in growth plates. These results, which parallel pediatric growth patterns, highlight the fundamental role of diet in the earliest stages of developing obesity-related skeletal complications and validate the utility of the model for future studies aimed at determining mechanisms of diet-enhanced bone lengthening.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarah Rubin ◽  
Ankit Agrawal ◽  
Johannes Stegmaier ◽  
Sharon Krief ◽  
Neta Felsenthal ◽  
...  

AbstractThe activity of epiphyseal growth plates, which drives long bone elongation, depends on extensive changes in chondrocyte size and shape during differentiation. Here, we develop a pipeline called 3D Morphometric Analysis for Phenotypic significance (3D MAPs), which combines light-sheet microscopy, segmentation algorithms and 3D morphometric analysis to characterize morphogenetic cellular behaviors while maintaining the spatial context of the growth plate. Using 3D MAPs, we create a 3D image database of hundreds of thousands of chondrocytes. Analysis reveals broad repertoire of morphological changes, growth strategies and cell organizations during differentiation. Moreover, identifying a reduction in Smad 1/5/9 activity together with multiple abnormalities in cell growth, shape and organization provides an explanation for the shortening of Gdf5 KO tibias. Overall, our findings provide insight into the morphological sequence that chondrocytes undergo during differentiation and highlight the ability of 3D MAPs to uncover cellular mechanisms that may regulate this process.


Author(s):  
Camilo López-Aguirre ◽  
Suzanne J. Hand ◽  
Daisuke Koyabu ◽  
Vuong Tan Tu ◽  
Laura A. B. Wilson

Fluctuating asymmetry (random fluctuations between the left and right sides of the body) has been interpreted as an index to quantify both the developmental instabilities and homeostatic capabilities of organisms, linking the phenotypic and genotypic aspects of morphogenesis. However, studying the ontogenesis of fluctuating asymmetry has been limited to mostly model organisms in postnatal stages, missing prenatal trajectories of asymmetry that could better elucidate decoupled developmental pathways controlling symmetric bone elongation and thickening. In this study, we quantified the presence and magnitude of asymmetry during the prenatal development of bats, focusing on the humerus, a highly specialized bone adapted in bats to perform under multiple functional demands. We deconstructed levels of asymmetry by measuring the longitudinal and cross-sectional asymmetry of the humerus using a combination of linear measurements and geometric morphometrics. We tested the presence of different types of asymmetry and calculated the magnitude of size-controlled fluctuating asymmetry to assess developmental instability. Statistical support for the presence of fluctuating asymmetry was found for both longitudinal and cross-sectional asymmetry, explaining on average 16% of asymmetric variation. Significant directional asymmetry accounted for less than 6.6% of asymmetric variation. Both measures of fluctuating asymmetry remained relatively stable throughout ontogeny, but cross-sectional asymmetry was significantly different across developmental stages. Finally, we did not find a correspondence between developmental patterns of longitudinal and cross-sectional asymmetry, indicating that processes promoting symmetrical bone elongation and thickening work independently. We suggest various functional pressures linked to newborn bats’ ecology associated with longitudinal (altricial flight capabilities) and cross-sectional (precocial clinging ability) developmental asymmetry differentially. We hypothesize that stable magnitudes of fluctuating asymmetry across development could indicate the presence of developmental mechanisms buffering developmental instability.


2021 ◽  
pp. dmm.048272
Author(s):  
Martin Biosse Duplan ◽  
Emilie Dambroise ◽  
Valentin Estibals ◽  
Joelle Veziers ◽  
Jérome Guicheux ◽  
...  

Achondroplasia (ACH), the most common form of dwarfism is caused by a missense mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3). The resulting increase in FGFR3 signaling perturbs the proliferation and differentiation of chondrocytes (CCs), alters the process of endochondral ossification and thus reduces bone elongation. Increased FGFR3 signaling in osteoblasts (OBs) might also contribute to bone anomalies in ACH. In the present study of a mouse model of ACH, we sought to determine whether or not FGFR3 overactivation in OBs leads to bone modifications. The model carries an Fgfr3 activating mutation (Fgfr3Y367C/+) that accurately mimics ACH; we targeted the mutation to either immature OBs and hypertrophic CCs or to mature OBs by using the Osx-cre and collagen 1α1 (2.3kb-Col1α1)-cre mouse strains, respectively. We observed that Fgfr3 activation in immature OBs and hypertrophic CCs (Osx-Fgfr3) not only perturbed the hypertrophic cells of the growth plate (thus affecting long bone growth) but also led to osteopenia and low cortical thickness in long bones in adult (3-month-old) mice but not in growing (3-week-old) mice. Importantly, craniofacial membranous bone defects were present in the adult mice. In contrast, activation of Fgfr3 in mature OBs (Col1-Fgfr3) had very limited effects on skeletal shape, size and micro-architecture. In vitro, we observed that Fgfr3 activation in immature OBs was associated with low mineralization activity. In conclusion, immature OBs appears to be affected by Fgfr3 overactivation, which might contribute to the bone modifications observed in ACH independently of CCs.


2021 ◽  
Author(s):  
L. Martin ◽  
N. Kaci ◽  
C. Benoist-Lasselin ◽  
M. Mondoloni ◽  
S. Decaudaveine ◽  
...  

AbstractA gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most frequent form of dwarfism. The constitutive activation of FGFR3 impaired bone formation and elongation and many signaling transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH. Natural plant compounds are the prime sources of drug candidates. Here, we found that the phenol compound (-)-epicatechin isolated from Theobroma cacao effectively inhibits FGFR3’s downstream signaling pathways. Transcriptomic analysis in Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian hedgehog and PKA pathways. (-)-Epicatechin is able to rescue impairments in the expression of these mRNA that control both the structural organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model (Fgfr3Y367C/+) of ACH, we showed that (-)-epicatechin countered the bone growth impairment during 6 days of ex vivo cultures. We confirmed in vivo that daily subcutaneous injections of (-)-epicatechin in Fgfr3Y367C/+ mice increased bone elongation and rescued the primary cilium defect observed in chondrocytes. This modification of the primary cilia promoted the typical columnar arrangement of flat proliferative chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study illustrated (-)-epicatechin’s ability may facilitate the development of (-)-epicatechin as a treatment for patients with ACH.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tomonori Ozaki ◽  
Tatsuya Kawamoto ◽  
Yuki Iimori ◽  
Nobuaki Takeshita ◽  
Yukiko Yamagishi ◽  
...  

AbstractAchondroplasia is caused by gain-of-function mutations in FGFR3 gene and leads to short-limb dwarfism. A stabilized analogue of C-type natriuretic peptide (CNP) is known to elongate bone by interacting with FGFR3 signals and thus is a promising drug candidate. However, it needs daily administration by percutaneous injection. FGFR inhibitor compounds are other drug candidates for achondroplasia because they directly fix the mutant protein malfunction. Although FGFR inhibitors elongate the bone of model mice, their adverse effects are not well studied. In this study, we found that a new FGFR inhibitor, ASP5878, which was originally developed as an anti-cancer drug, elongated the bone of achondroplasia model male mice at the dose of 300 μg/kg, which confers an AUC of 275 ng·h/ml in juvenile mice. Although ASP5878 was less effective in bone elongation than a CNP analogue, it is advantageous in that ASP5878 can be administered orally. The AUC at which minimal adverse effects were observed (very slight atrophy of the corneal epithelium) was 459 ng·h/ml in juvenile rats. The positive discrepancy between AUCs that brought efficacy and minimal adverse effect suggests the applicability of ASP5878 to achondroplasia in the clinical setting. We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests.


2020 ◽  
pp. 29-42
Author(s):  
Sončka Jazbinšek ◽  
Primož Kotnik

Linear growth is the result of bone elongation in children and adolescents mediated by processes of endochondral ossification and maturation of bone tissue. Physical activity (PA) importantly influences both processes through systemic and local effects, mediated by growth hormone, insulin-like factor I, sex hormones, thyroid hormones, glucocorticoid hormones and various cytokines with endo-, para- and autocrine function, secreted by adipose tissue (adipokines) or muscles (myokines). It is important to promote a physically active lifestyle already in early childhood as it tends to persist into adulthood together with favorable body composition. From the safety point-of-view, recent data suggests that PA does not negatively influence linear growth regardless of its duration or intensity, as long as chronic negative energy balance is prevented by sufficient energy intake. The aim of this review is to describe current scientific knowledge on the mechanisms by which PA could influence linear growth and present recent studies analyzing its possible effects.


2020 ◽  
Vol 18 (3) ◽  
pp. 210-227
Author(s):  
Holly L. Racine ◽  
Maria A. Serrat
Keyword(s):  

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Benoit Demuynck ◽  
Justine Filipo ◽  
Gary Li ◽  
Carl L Dambkowski ◽  
Laurence Legeai-Mallet

Abstract Background: Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia. Fibroblast growth factor receptor 3 (FGFR3) plays a crucial role in bone elongation, demonstrated by FGFR3 gain-of-function mutations in individuals with ACH and hypochondroplasia. Multiple therapeutic strategies have been considered for ACH, the most advanced is to employ an analog of C-type Natriuretic Peptide (CNP), which antagonizes the MAP kinase (MAPK) pathway. Here, we evaluated a therapeutic strategy that targets all pathways downstream of FGFR3 (e.g., STAT1), not just MAPK. We hypothesized that a very low dose of the oral selective FGFR1-3 tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) would be able to improve defective bone elongation. We also hypothesized that infigratinib would have greater potency at lower concentrations in an ACH cell line than a CNP analog (e.g., vosoritide) given its effects on multiple downstream pathways. Methods: A mouse model (Fgfr3Y367C/+) mimicking ACH was treated with subcutaneous injections of infigratinib daily (0.2 or 0.5 mg/kg/day) or intermittently (1 mg/kg, every 3 days) for a treatment duration of 15 days (PND1-15). In vivo results were compared with vehicle-treated mutant mice. TAN 4-18-chondrocytes, a human chondrocyte line expressing a heterozygous Y373C FGFR3 mutation, were treated with multiple concentrations of infigratinib and vosoritide and MAPK levels were measured. Results: We observed a significant improvement of the upper (humerus +7%, ulna +11%) and lower (femur +11%, tibia +16%) limbs at 0.5 mg/kg/day, and improvement in the foramen magnum. The effect of infigratinib on bone elongation was reduced with a lower dose (0.2 mg/kg), confirming a dose-response relationship. With intermittent injections of infigratinib (1 mg/kg, every 3 days), gain of growth was significant for all the long bones (+7%) and the size of the foramen magnum was increased. Modification of the growth plate structure, displaying better organization, was also seen. In cell line data, compared with FGF18-treated TAN 4-18-chondrocytes, concentrations of 10-6M to 10-10M infigratinib led to statistically significant (p<0.05) improvements. With vosoritide treatment, a concentration of 10-4M led to statistically significant improvements compared with FGF18-treated chondrocytes (p<0.05), although this was not seen at 10-5M. Conclusions: Preclinical ACH mouse model data indicate that low, as well as intermittent, doses of infigratinib promote growth and can improve the foramen magnum. No apparent toxicity of infigratinib was observed, suggesting that TKI therapy has the potential to be a valuable and relevant option for children with ACH. Furthermore, cell line data indicate that infigratinib showed superior potency over a CNP analog, suggesting that inhibition of multiple FGFR3-related pathways vs MAPK inhibition alone may lead to increased efficacy.


Sign in / Sign up

Export Citation Format

Share Document