Targeting sulfation-dependent mechanoreciprocity between matrix and osteoblasts to mitigate bone loss
Targeting sulfation-dependent mechanoreciprocity between matrix and osteoblasts to mitigate bone loss
复制标题
DOI：
10.1126/scitranslmed.adg3983
复制
发表时间：
2023-08-23
影响因子：
17.1
通讯作者：
Yang，Liu
中科院分区：
文献类型：
--
作者：
Zheng，Chao;Liu，He;Yang，Liu
硫酸盐化是生物分子的一种广泛的修饰，到目前为止还没有被完全探索过。通过对多达426,824名基因分型的人类参与者的交叉表型荟萃分析以及多个突变小鼠品系的表型特征，我们确定了硫酸盐转运体溶质载体家族26成员A2(SLC26A2)缺乏在骨质疏松症中的致病作用。去除成骨细胞中的SLC26A2会导致严重的骨丢失和未成熟骨细胞的堆积，并引发特殊的细胞外基质(PCM)的产生，其特征是硫酸盐化不足和硬度降低。这些改变的PCM的化学物理性质破坏了成骨细胞局部粘连的形成。大量RNA测序和功能分析表明，粘着斑激酶(FAK)和YES1相关转录调节因子(YAP)/含转录调节因子1(TAZ)的WW结构域信号的机械反应性抑制在SLC26A2缺乏时影响成骨细胞的成熟。此外，药理上取消河马激酶和强迫轮转通过促进YAP/TAZ活性来改善SLC26A2缺乏性骨质疏松症。对小鼠单细胞RNA测序数据的分析表明，在成骨细胞向骨细胞的转变过程中，硫酸盐代谢、焦点黏附和YAP/TAZ活性之间存在协调。除SLC26A2缺陷外，在去卵巢小鼠和骨质疏松患者的骨细胞中也观察到FAK和YAP/TAZ信号的改变，YAP/TAZ活性的药理作用改善了去卵巢小鼠的骨丢失。总而言之，这些数据揭示了硫酸盐化在基质和成骨细胞之间的发育机械相互作用中的作用，这可以被用来防止骨丢失。
Sulfation is a widespread modification of biomolecules that has been incompletely explored to date. Through cross-phenotype meta-analysis of bone mineral density in up to 426,824 genotyped human participants along with phenotypic characterization of multiple mutant mouse lines, we identified a causative role for sulfate transporter solute carrier family 26 member A2 (SLC26A2) deficiency in osteoporosis. Ablation ofSLC26A2in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited peculiar pericellular matrix (PCM) production characterized by undersulfation coupled with decreased stiffness. These altered chemophysical properties of the PCM disrupted the formation of focal adhesions in osteoblasts. Bulk RNA sequencing and functional assays revealed that the mechanoreciprocal inhibition of focal adhesion kinase (FAK) and Yes1-associated transcriptional regulator (YAP)/WW domain containing transcription regulator 1 (TAZ) signaling impinged osteoblast maturation uponSLC26A2deficiency. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running amelioratedSLC26A2-deficient osteoporosis by promoting YAP/TAZ activity. Analysis of mouse single-cell RNA sequencing data suggested coordination among sulfate metabolism, focal adhesion, and YAP/TAZ activity during osteoblast-to-osteocyte transition. In addition to theSLC26A2-deficient setting, altered FAK and YAP/TAZ signaling was also observed in bone cells of ovariectomized mice and patients with osteoporosis, and pharmacological enforcing of YAP/TAZ activity ameliorated bone loss in ovariectomized mice. Collectively, these data unveil a role for sulfation in the developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss.