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1. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasiasResearch in context

Author

Chao Zheng, Xisheng Lin, Xiaolong Xu, Cheng Wang, Jinru Zhou, Bo Gao, Jing Fan, Weiguang Lu, Yaqian Hu, Qiang Jie, Zhuojing Luo, and Liu Yang

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: 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. Methods: 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. Findings: 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. Interpretation: 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). Keywords: SLC26A2, Achondrogenesis type 1B, Atelosteogenesis type 2, Collagen secretion, FGFR3 signaling

Published
2019
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2. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias

Author

Weiguang Lu, Lin Xisheng, Cheng Wang, Zhuojing Luo, Jing Fan, Jinru Zhou, Qiang Jie, Chao Zheng, Liu Yang, Yaqian Hu, Xiaolong Xu, and Bo Gao

Subjects
0301 basic medicine, musculoskeletal diseases, Research paper, Atelosteogenesis type 2, SLC26A2, Osteochondrodysplasias, General Biochemistry, Genetics and Molecular Biology, Achondroplasia, Achondrogenesis type 1B, 03 medical and health sciences, Mice, 0302 clinical medicine, Chondrocytes, Atelosteogenesis, type II, FGFR3 signaling, medicine, Morphogenesis, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 3, Growth Plate, Mice, Knockout, biology, Cell growth, ATF6, Gene Expression Regulation, Developmental, Cell Differentiation, General Medicine, medicine.disease, musculoskeletal system, Cell biology, Activating Transcription Factor 6, Disease Models, Animal, 030104 developmental biology, Cartilage, Phenotype, Apoptosis, Fibroblast growth factor receptor, Sulfate Transporters, 030220 oncology & carcinogenesis, Mutation, biology.protein, Unfolded protein response, Unfolded Protein Response, Phosphorylation, Disease Susceptibility, Collagen secretion, Signal Transduction
Abstract

Background 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. Methods 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. Findings 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. Interpretation 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).

Published
2019

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