Suppressing UPR-Dependent Overactivation of FGFR3 Signaling Ameliorates SLC26A2-Deficient Chondrodysplasias

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 skeletonspecific pathology, we generated and analyzed slc26a2 −/− and Col2a1-Cre; slc26a2 fl/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; slc26a2 fl/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.

Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-α-driven inflammation and ER stress

“…OA is a complex process of joint degeneration that is regulated by multiple factors, such as inflammatory mediators, mechanical forces, and transcriptional regulators [35]. Several epigenetic alterations, including the acetylation, methylation, ubiquitination, and phosphorylation of histone, have been shown to play important roles in the pathogenesis of OA [16,18,36,37]. Among them, the acetylation balance of histone mediated by HATs and HDACs is associated with the activation and inhibition of gene transcription in chondrocyte homeostasis [18].…”

Phenotypic characterization of Slc26a2 mutant mice reveals a multifactorial etiology of spondylolysis

“…Besides the D673V mutant mouse line, Col1a1 2.3kb‐Cre mice were crossbred with Slc26a2‐loxP and R26 tdTomato mice to generate Col1a1‐Cre; Slc26a2 fl/fl mice and trace Cre‐expressing cells in vivo, respectively. Col1a1 2.3kb‐Cre , Slc26a2‐loxP , and R26 tdTomato mice were genotyped according to previous studies . Animal care and experiments were performed in accordance with protocols approved by the Ethics in Animal Research Committee of the Fourth Military Medical University.…”

“…Col1a1 2.3kb-Cre, Slc26a2-loxP, and R26 tdTomato mice were genotyped according to previous studies. [30][31][32] Animal care and experiments were performed in accordance with protocols approved by the Ethics in Animal Research Committee of the Fourth Military Medical University.…”

“…[24][25][26] They anchor or transduce a myriad of growth factor signals through direct interactions, orchestrate matrix assembly, and maintain mechanical properties of extracellular matrix, which is required for proper endochondral ossification. [22][23][24]27 Particularly, in addition to impaired linear bone growth of appendicular skeleton, patients with diastrophic dysplasia and mouse models deficient for Slc26a2 are often associated with spinal deformities of varying clinical severity, 20,[28][29][30] including abnormal ossification and clefts of lumbar vertebrae, decreased interpedicular distance, scoliosis, cervical kyphosis, and lumbar lordosis, which suggests a potentially associated pathogenesis of chondrodysplasias and inherited spondylolysis.…”

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

“…Even if sulfate uptake from the extracellular environment is crucial for PG sulfation, alternative pathways of sulfate recruitment from intracellular thiol compounds have been demonstrated in the dtd mouse suggesting potential pharmacological approaches to DTD . Recently a Slc26a2 knock‐out mouse has been generated as a model of ACG1B and AO2, and an overactivation of FGFR3 signalling has been demonstrated and proposed as a pathogenic mechanism contributing to the lethal skeletal phenotype .…”