Imren Gozde, Karaosmanoglu Beren, Muratoglu Bihter, Ozdemir Cansu, Utine Gulen Eda, Simsek-Kiper Pelin Ozlem, Taskiran Ekim Z
Department of Medical Genetics, Faculty of Medicine, Hacettepe University, 06100 Ankara, Türkiye.
Department of Medical and Surgical Research, Institute of Health Sciences, Hacettepe University, 06100 Ankara, Türkiye.
Int J Mol Sci. 2025 Jan 28;26(3):1134. doi: 10.3390/ijms26031134.
Skeletal dysplasias, characterized by bone, cartilage, and connective tissue abnormalities, often arise due to disruptions in extracellular matrix (ECM) dynamics and growth factor-dependent signaling pathways. RSPRY1, a secreted protein with RING and SPRY domains, has been implicated in bone development, yet its exact role remains to be determined. gene mutations are associated with spondyloepimetaphyseal dysplasia (SEMD), a rare skeletal disorder characterized by severe epiphyseal and metaphyseal deformities. This study aimed to determine the molecular and cellular mechanisms by which RSPRY1 deficiency affects skeletal homeostasis. Transcriptome analysis of fibroblasts from patients with homozygous mutations showed there was significant enrichment of transforming growth factor beta (TGF-β) signaling and ECM-related pathways. Functional wound healing assays showed that knockout fibroblasts exhibited enhanced motility, a phenotype that was abrogated in + double knockout fibroblasts, highlighting the SMAD3-dependence of RSPRY1's effects. The observed limited response to exogenous TGF-β in RSPRY1-deficient cells indicated that there was constitutive pathway activation. These findings show that RSPRY1 is a critical regulator of TGF-β signaling in ECM dynamics and cell motility, contributing to the pathophysiology of SEMD. An improvement in our understanding of the molecular roles of RSPRY1 might yield novel therapeutic strategies that target TGF-β signaling in patients with SEMD and other skeletal dysplasias.
骨骼发育异常以骨骼、软骨和结缔组织异常为特征，通常是由于细胞外基质（ECM）动态变化和生长因子依赖性信号通路的破坏所致。RSPRY1是一种具有RING和SPRY结构域的分泌蛋白，与骨骼发育有关，但其确切作用仍有待确定。基因突变与脊椎骨骺发育异常（SEMD）相关，这是一种罕见的骨骼疾病，其特征是严重的骨骺和干骺端畸形。本研究旨在确定RSPRY1缺乏影响骨骼稳态的分子和细胞机制。对纯合基因突变患者的成纤维细胞进行转录组分析表明，转化生长因子β（TGF-β）信号通路和ECM相关通路有显著富集。功能性伤口愈合试验表明，敲除成纤维细胞表现出增强的运动性，这种表型在RSPRY1+SMAD3双敲除成纤维细胞中被消除，突出了RSPRY1作用对SMAD3的依赖性。在RSPRY1缺陷细胞中观察到对外源TGF-β的有限反应，表明存在组成型信号通路激活。这些发现表明，RSPRY1是ECM动态变化和细胞运动中TGF-β信号通路的关键调节因子，对SEMD的病理生理学有影响。更好地理解RSPRY1的分子作用可能会产生针对SEMD和其他骨骼发育异常患者的TGF-β信号通路的新治疗策略。
