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- W2913359674 abstract "Mutations in the SLC26A2 gene cause a spectrum of currently incurable human chondrodysplasias. However, genotype-phenotype relationships of SLC26A2-deficient chondrodysplasias are still perplexing and thus stunt therapeutic development.To investigate the causative role of SLC26A2 deficiency in chondrodysplasias and confirm its skeleton-specific pathology, we generated and analyzed slc26a2-/- and Col2a1-Cre; slc26a2fl/fl mice. The therapeutic effect of NVP-BGJ398, an FGFR inhibitor, was tested with both explant cultures and timed pregnant females.Two lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2-/- mice. Unexpectedly, slc26a2-/- chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2-/- chondrocytes. Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2-/- cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis. Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2-/- newborns. Finally, we confirm the skeleton-specific lethality and pathology of global SLC26A2 deletion through analyzing the Col2a1-Cre; slc26a2fl/fl mouse line.Our study unveils a previously unrecognized pathogenic mechanism underlying ACG1B and AO2, and supports suppression of FGFR3 signaling as a promising therapeutic approach for SLC26A2-related chondrodysplasias. FUND: This work was supported by National Natural Science Foundation of China (81871743, 81730065 and 81772377)." @default.
- W2913359674 created "2019-02-21" @default.
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- W2913359674 date "2019-02-01" @default.
- W2913359674 modified "2023-10-10" @default.
- W2913359674 title "Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias" @default.
- W2913359674 cites W1678102090 @default.
- W2913359674 cites W1855766111 @default.
- W2913359674 cites W1921172676 @default.
- W2913359674 cites W1974864561 @default.
- W2913359674 cites W1977603207 @default.
- W2913359674 cites W1979512964 @default.
- W2913359674 cites W1981284961 @default.
- W2913359674 cites W1981701016 @default.
- W2913359674 cites W1982406124 @default.
- W2913359674 cites W1988558800 @default.
- W2913359674 cites W1993847445 @default.
- W2913359674 cites W1999559618 @default.
- W2913359674 cites W2001399725 @default.
- W2913359674 cites W2003096043 @default.
- W2913359674 cites W2003305541 @default.
- W2913359674 cites W2003588740 @default.
- W2913359674 cites W2003621498 @default.
- W2913359674 cites W2005235985 @default.
- W2913359674 cites W2014949148 @default.
- W2913359674 cites W2019849438 @default.
- W2913359674 cites W2034140040 @default.
- W2913359674 cites W2037318608 @default.
- W2913359674 cites W2038088062 @default.
- W2913359674 cites W2040325305 @default.
- W2913359674 cites W2041632453 @default.
- W2913359674 cites W2042932723 @default.
- W2913359674 cites W2043484559 @default.
- W2913359674 cites W2049361908 @default.
- W2913359674 cites W2058877705 @default.
- W2913359674 cites W2062159807 @default.
- W2913359674 cites W2068251671 @default.
- W2913359674 cites W2068896961 @default.
- W2913359674 cites W2072288858 @default.
- W2913359674 cites W2076958216 @default.
- W2913359674 cites W2083248417 @default.
- W2913359674 cites W2095504053 @default.
- W2913359674 cites W2096589680 @default.
- W2913359674 cites W2099096748 @default.
- W2913359674 cites W2103051141 @default.
- W2913359674 cites W2108644248 @default.
- W2913359674 cites W2108821991 @default.
- W2913359674 cites W2109043636 @default.
- W2913359674 cites W2109474038 @default.
- W2913359674 cites W2113988225 @default.
- W2913359674 cites W2118601769 @default.
- W2913359674 cites W2119154062 @default.
- W2913359674 cites W2119521806 @default.
- W2913359674 cites W2121360268 @default.
- W2913359674 cites W2122873246 @default.
- W2913359674 cites W2123629596 @default.
- W2913359674 cites W2123936301 @default.
- W2913359674 cites W2124246726 @default.
- W2913359674 cites W2129465868 @default.
- W2913359674 cites W2130326770 @default.
- W2913359674 cites W2141843510 @default.
- W2913359674 cites W2145913206 @default.
- W2913359674 cites W2154917734 @default.
- W2913359674 cites W2157697960 @default.
- W2913359674 cites W2158250449 @default.
- W2913359674 cites W2162695817 @default.
- W2913359674 cites W2169236340 @default.
- W2913359674 cites W2169458613 @default.
- W2913359674 cites W2292575708 @default.
- W2913359674 cites W2302830369 @default.
- W2913359674 cites W2309578770 @default.
- W2913359674 cites W2319017331 @default.
- W2913359674 cites W2337634448 @default.
- W2913359674 cites W2401913845 @default.
- W2913359674 cites W2514574167 @default.
- W2913359674 cites W2515216392 @default.
- W2913359674 cites W2528851536 @default.
- W2913359674 cites W2561993249 @default.
- W2913359674 cites W2571952841 @default.
- W2913359674 cites W2604078450 @default.
- W2913359674 cites W2756268048 @default.
- W2913359674 cites W2793350909 @default.
- W2913359674 cites W2883916878 @default.
- W2913359674 cites W2994593180 @default.
- W2913359674 cites W605164714 @default.
- W2913359674 doi "https://doi.org/10.1016/j.ebiom.2019.01.010" @default.
- W2913359674 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6413327" @default.