Achondroplasia: Development, pathogenesis, and therapy

Ornitz, David M.; Legeai-Mallet, Laurence

doi:10.1002/dvdy.24479

Cited by 172 publications

(182 citation statements)

References 247 publications

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“…Exposure to hormones or paracrine factors known to antagonize the actions of GC-B by activating G protein coupled receptors also leads to the dephosphorylation [21,25,43] and inactivation [22, 23, 27, 35, 39, 40, 46, 47] of GC-B in other cell types. However, except for a study of luteinizing hormone action on ovarian follicles [25], these previous studies did not couple changes in GC-B phosphorylation to physiological events.…”

Section: Discussionmentioning

confidence: 99%

“…However, except for a study of luteinizing hormone action on ovarian follicles [25], these previous studies did not couple changes in GC-B phosphorylation to physiological events. The present study links GC-B dephosphorylation and inactivation by a growth factor receptor to mechanisms that regulate bone growth [6,10].…”

Section: Discussionmentioning

confidence: 99%

“…Multiple mechanisms could contribute to FGFR3 regulation of long bone growth [25], including FGF inhibition of GC-B [26]. However, although FGF2 exposure was shown to inactivate GC-B in the ATDC5 chondrocyte cell line [26] and in BALB/3T3 fibroblasts [27], the molecular basis for the inactivation was not determined.…”

Section: Introductionmentioning

confidence: 99%

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Dephosphorylation is the mechanism of fibroblast growth factor inhibition of guanylyl cyclase-B

Robinson

Egbert

Davydova

et al. 2017

Cellular Signalling

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Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations of guanylyl cyclase-B (GC-B, also called NPRB or NPR2) cause dwarfism. FGF exposure inhibits GC-B activity in a chondrocyte cell line, but the mechanism of the inactivation is not known. Here, we report that FGF exposure causes dephosphorylation of GC-B in rat chondrosarcoma cells, which correlates with a rapid, potent and reversible inhibition of C-type natriuretic peptide-dependent activation of GC-B. Cells expressing a phosphomimetic mutant of GC-B that cannot be inactivated by dephosphorylation because it contains glutamate substitutions for all known phosphorylation sites showed no decrease in GC-B activity in response to FGF. We conclude that FGF rapidly inactivates GC-B by a reversible dephosphorylation mechanism, which may contribute to the signaling network by which activated FGFR3 causes dwarfism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dephosphorylation is the mechanism of fibroblast growth factor inhibition of guanylyl cyclase-B

Robinson

Egbert

Davydova

et al. 2017

Cellular Signalling

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“…The growth plate is a major tissue responsible for long bone formation, morphogenesis, and growth in embryonic and postnatal skeletogenesis. Genetic and acquired abnormality of the growth plate causes various types of skeletal disorders . A key role of the growth plate in skeletal growth is to provide the longitudinal and transverse space and environment to newly forming bone.…”

Section: Introductionmentioning

confidence: 99%

Possible Contribution of Wnt-Responsive Chondroprogenitors to the Postnatal Murine Growth Plate

Usami

Gunawardena

Francois

et al. 2019

Journal of Bone and Mineral Research

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Active cell proliferation and turnover in the growth plate is essential for embryonic and postnatal bone growth. We performed a lineage tracing of Wnt/β‐catenin signaling responsive cells (Wnt‐responsive cells) using Axin2CreERT2;Rosa26ZsGreen mice and found a novel cell population that resides in the outermost layer of the growth plate facing the Ranvier's groove (RG; the perichondrium adjacent to growth plate). These Wnt‐responsive cells rapidly expanded and contributed to formation of the outer growth plate from the neonatal to the growing stage but stopped expanding at the young adult stage when bone longitudinal growth ceases. In addition, a second Wnt‐responsive sporadic cell population was localized within the resting zone of the central part of the growth plate during the postnatal growth phase. While it induced ectopic chondrogenesis in the RG, ablation of β‐catenin in the Wnt‐responsive cells strongly inhibited expansion of their descendants toward the growth plate. These findings indicate that the Wnt‐responsive cell population in the outermost layer of the growth plate is a unique cell source of chondroprogenitors involving lateral growth of the growth plate and suggest that Wnt/β‐catenin signaling regulates function of skeletal progenitors in a site‐ and stage‐specific manner. © 2019 American Society for Bone and Mineral Research.

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“…These mutations result in ligand‐dependent activation of the mutant FGFR and, in some cases, change in the ligand binding specificity of the FGFR. The only documented example of a FGFR loss‐of‐function mutation occurs in CATSHL syndrome, in which loss of FGFR3 results in skeletal overgrowth due to increased chondrogenesis …”

Section: Introductionmentioning

confidence: 99%

Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes

McKenzie

Smith

Karuppaiah

et al. 2019

Journal of Bone and Mineral Research

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Fibroblast growth factor (FGF) signaling pathways have well‐established roles in skeletal development, with essential functions in both chondrogenesis and osteogenesis. In mice, previous conditional knockout studies suggested distinct roles for FGF receptor 1 (FGFR1) signaling at different stages of osteogenesis and a role for FGFR2 in osteoblast maturation. However, the potential for redundancy among FGFRs and the mechanisms and consequences of stage‐specific osteoblast lineage regulation were not addressed. Here, we conditionally inactivate Fgfr1 and Fgfr2 in mature osteoblasts with an Osteocalcin (OC)‐Cre or Dentin matrix protein 1 (Dmp1)‐CreER driver. We find that young mice lacking both receptors or only FGFR1 are phenotypically normal. However, between 6 and 12 weeks of age, OC‐Cre Fgfr1/Fgfr2 double‐ and Fgfr1 single‐conditional knockout mice develop a high bone mass phenotype with increased periosteal apposition, increased and disorganized endocortical bone with increased porosity, and biomechanical properties that reflect increased bone mass but impaired material properties. Histopathological and gene expression analyses show that this phenotype is preceded by a striking loss of osteocytes and accompanied by activation of the Wnt/β‐catenin signaling pathway. These data identify a role for FGFR1 signaling in mature osteoblasts/osteocytes that is directly or indirectly required for osteocyte survival and regulation of bone mass during postnatal bone growth. © 2019 American Society for Bone and Mineral Research.

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Achondroplasia: Development, pathogenesis, and therapy

Cited by 172 publications

References 247 publications

Dephosphorylation is the mechanism of fibroblast growth factor inhibition of guanylyl cyclase-B

Dephosphorylation is the mechanism of fibroblast growth factor inhibition of guanylyl cyclase-B

Possible Contribution of Wnt-Responsive Chondroprogenitors to the Postnatal Murine Growth Plate

Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes

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