Platko Khrystyna, Gyulay Gabriel, Lebeau Paul F, MacDonald Melissa E, Lynn Edward G, Byun Jae Hyun, Igdoura Suleiman A, Holden Rachel M, Roubtsova Anna, Seidah Nabil G, Krepinsky Joan C, Austin Richard C
Department of Medicine, Division of Nephrology, McMaster University, and The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada.
Department of Biology, McMaster University Medical Centre, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
J Biol Chem. 2024 Nov;300(11):107805. doi: 10.1016/j.jbc.2024.107805. Epub 2024 Sep 21.
Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) as a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death-associated gene 51 (TDAG51) expression leads to an attenuation of medial VC. We now show a significant induction of circulating levels of growth differentiation factor 10 (GDF10) in TDAG51 mice, which was of interest due to its established role as an inhibitor of osteoblast differentiation. The objective of this study was to examine the role of GDF10 in the osteogenic transdifferentiation of VSMCs. Using primary mouse and human VSMCs, as well as ex vivo aortic ring cultures, we demonstrated that treatment with recombinant human (rh) GDF10 mitigated phosphate-mediated hydroxyapatite (HA) mineral deposition. Furthermore, ex vivo aortic rings from GDF10 mice exhibited increased HA deposition compared to C57BL/6J controls. To explain our observations, we identified that rhGDF10 treatment reduced protein expression of runt-related transcription factor 2, a key driver of osteogenic transdifferentiation of VSMCs and VC. In support of these findings, in vivo treatment with rhGDF10 attenuated VD-induced VC. Furthermore, we demonstrated an increase in circulating GDF10 in patients with chronic kidney disease with clinically defined severe VC, as assessed by coronary artery calcium score. Thus, our studies identify GDF10 as a novel inhibitor of mineral deposition and as such, may represent a potential novel biomarker and therapeutic target for the detection and management of VC.
心血管疾病死亡率在慢性肾脏病患者中尤其高且呈上升趋势，血管钙化（VC）是其主要病理生理特征。VC是一个高度受调控的生物学过程，类似于涉及血管平滑肌细胞（VSMC）成骨转分化的骨形成过程。我们之前已经证明，T细胞死亡相关基因51（TDAG51）表达缺失会导致中膜VC减轻。我们现在发现，TDAG51基因敲除小鼠循环中生长分化因子10（GDF10）水平显著升高，鉴于其作为成骨细胞分化抑制剂的既定作用，这一发现很有意思。本研究的目的是探讨GDF10在VSMC成骨转分化中的作用。使用原代小鼠和人VSMC以及离体主动脉环培养，我们证明重组人（rh）GDF10处理可减轻磷酸盐介导的羟基磷灰石（HA）矿物质沉积。此外，与C57BL/6J对照组相比，GDF10基因敲除小鼠的离体主动脉环显示HA沉积增加。为了解释我们的观察结果，我们发现rhGDF10处理降低了 runt相关转录因子2的蛋白表达，runt相关转录因子2是VSMC成骨转分化和VC的关键驱动因子。支持这些发现的是，rhGDF10体内处理减轻了维生素D诱导的VC。此外，通过冠状动脉钙化评分评估，我们证明临床定义为严重VC的慢性肾脏病患者循环中GDF10增加。因此，我们的研究确定GDF10是矿物质沉积的新型抑制剂，因此可能代表检测和管理VC的潜在新型生物标志物和治疗靶点。
