Meckel’s and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible

Duplan, Martin Biosse; Komla-Ebri, Davide; Heuzé, Yann; Estibals, Valentin; Gaudas, Emilie; Kaci, Nabil; Benoist-Lasselin, Catherine; Zérah, Michel; Krämer, Ina; Kneissel, Michaela; Porta, Diana Grauss; Rocco, Federico Di; Legeai-Mallet, Laurence

doi:10.1093/hmg/ddw153

Cited by 27 publications

(33 citation statements)

References 61 publications

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“…For example, in the Fgfr3-K644E mouse model, enhanced proliferation of chondrocytes was detected in the growth plate during a limited period in the early stages of endochondral ossification, whereas a decreased chondrocyte differentiation was observed all along the bone development (19). A similar conclusion was made in the Fgfr3-Y367C mouse model for the growth plate and for Meckel's cartilage (20,21). In our study, we observed this increase of proliferation at birth; this latter could, however, also occur during a limited period but cannot be detected because Adamtsl2 KO mice die at birth.…”

Section: Discussionsupporting

confidence: 54%

Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency

et al. 2018

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Mutations in the a disintegrin and metalloproteinase with thrombospondin motif–like 2 (ADAMTSL2) gene are responsible for the autosomal recessive form of geleophysic dysplasia, which is characterized by short stature, short extremities, and skeletal abnormalities. However, the exact function of ADAMTSL2 is unknown. To elucidate the role of this protein in skeletal development, we generated complementary knockout (KO) mouse models with either total or chondrocyte Adamtsl2 deficiency. We observed that the Adamtsl2 KO mice displayed skeletal abnormalities reminiscent of the human phenotype. Adamtsl2 deletion affected the growth plate formation with abnormal differentiation and proliferation of chondrocytes. In addition, a TGF‐β signaling impairment in limbs lacking Adamtsl2 was demonstrated. Further investigations revealed that Adamtsl2 KO chondrocytes failed to establish a microfibrillar network composed by fibrillin1 and latent TGF‐β binding protein 1 fibrils. Chondrocyte Adamtsl2 KO mice also exhibited dwarfism. These studies uncover the function of Adamtsl2 in the maintenance of the growth plate ECM by modulating the microfibrillar network.—Delhon, L., Mahaut, C., Goudin, N., Gaudas, E., Piquand, K., Le Goff, W., Cormier‐Daire, V., Le Goff, C. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency. FASEB J. 33, 2707–2718 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 54%

Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency

et al. 2018

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“…However, it is not yet known whether Fgfr2 is solely responsible for FGF-mediated regulation of Scx + /Sox9 + cells. Fgfr1 and Fgfr3 are restricted to chondroblastic and hypertrophic layers within the postnatal condylar cartilage and Fgfr3 signaling regulates chondrocyte maturation in the condyle (Duplan et al, 2016;Fuentes et al, 2002;Yasuda et al, 2012). Thus, these FGFR family proteins have the potential to regulate eminence formation within the tendon-bone attachment units of the mandible.…”

Section: Discussionmentioning

confidence: 99%

FGF signaling patterns cell fate at the interface between tendon and bone

et al. 2019

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Tendon and bone are attached by a transitional connective tissue that is morphologically graded from tendinous to osseous and develops from bipotent progenitors that co-express scleraxis (Scx) and Sox9 (Scx + /Sox9 +). Scx + /Sox9 + progenitors have the potential to differentiate into either tenocytes or chondrocytes, yet the developmental mechanism that spatially resolves their bipotency at the tendon-bone interface during embryogenesis remains unknown. Here, we demonstrate that development of Scx + /Sox9 + progenitors within the mammalian lower jaw requires FGF signaling. We find that loss of Fgfr2 in the mouse tendon-bone interface reduces Scx expression in Scx + /Sox9 + progenitors and induces their biased differentiation into Sox9 + chondrocytes. This expansion of Sox9 + chondrocytes, which is concomitant with decreased Notch2-Dll1 signaling, prevents formation of a mixed population of chondrocytes and tenocytes, and instead results in ectopic endochondral bone at tendon-bone attachment units. Our work shows that FGF signaling directs zonal patterning at the boundary between tendon and bone by regulating cell fate decisions through a mechanism that employs Notch signaling.

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“…Fgf18 disruption causes defective calvarial development (Ohbayashi et al, ). Both Fgfr3 inactivation and overactivation can lead to skeletal abnormalities in craniofacial regions (Biosse Duplan et al, ; Yu et al, ). In this study, we took advantage of Dmp1 Cre and R26R Fgf8 mice to activate FGF8 signaling in osteocytes during embryonic development.…”

Section: Discussionmentioning

confidence: 99%

Exogenous FGF8 signaling in osteocytes leads to mandibular hypoplasia in mice

Wang

Huang

et al. 2020

Oral Diseases

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Objective Fibroblast growth factor 8 (FGF8) signaling is essential in regulating craniofacial osteogenesis. This study aims to explore the effect of altered FGF8 signaling in maxillomandibular development during embryogenesis. Materials and Methods Dmp1Cre;R26RmTmG mice were generated to trace Dmp1+ cell lineage, and Dmp1Cre;R26RFgf8 mice were generated to explore the effects of augmented FGF8 signaling in Dmp1+ cells on osteogenesis with a focus on maxillomandibular development during embryogenesis, as assessed by whole mount skeletal staining, histology, and immunostaining. Additionally, cell proliferation rate and the expression of osteogenic genes were examined. Results Osteocytes of maxillomandibular bones were found Dmp1‐positive prenatally, and Fgf8 over‐expression in Dmp1+ cells led to mandibular hypoplasia. While Dmp1Cre allele functions in the osteocytes of the developing mandibular bone at as early as E13.5, and enhanced cell proliferation rate is observed in the bone forming region of the mandible in Dmp1Cre;R26RFgf8 mice at E14.5, histological examination showed that osteogenesis was initially impacted at E15.5, along with an inhibition of osteogenic differentiation markers. Conclusions Augmented FGF8 signaling in Dmp1+ cells lead to osteogenic deficiency in the mandibular bones, resulting in mandibular hypoplasia.

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Meckel’s and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible

Cited by 27 publications

References 61 publications

Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency

Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency

FGF signaling patterns cell fate at the interface between tendon and bone

Exogenous FGF8 signaling in osteocytes leads to mandibular hypoplasia in mice

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