Abstract:
Fibrous dysplasia (FD) is a skeletal stem cell disease caused by mutations in the guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene, which results in the abnormal accumulation of cyclic adenosine monophosphate (cAMP) and hyperactivation of downstream signaling pathways. Parathyroid hormone-related protein (PTHrP) is secreted by the osteoblast lineage and is involved in various physiological and pathological activities of bone. However, the association between the abnormal expression of PTHrP and FD, as well as its underlying mechanism, remains unclear. In this study, we discovered that FD patient-derived bone marrow stromal cells (FD BMSCs) expressed significantly higher levels of PTHrP during osteogenic differentiation and exhibited greater proliferation capacity but impaired osteogenic ability compared to normal control patient-derived BMSCs (NC BMSCs). Continuous exogenous PTHrP exposure on the NC BMSCs promoted the FD phenotype in both in vitro and in vivo experiments. Through the PTHrP/cAMP/PKA axis, PTHrP could partially influence the proliferation and osteogenesis capacity of FD BMSCs via the overactivation of the Wnt/β-Catenin signaling pathway. Furthermore, PTHrP not only directly modulated cAMP/PKA/CREB transduction but was also demonstrated as a transcriptional target of CREB. This study provides novel insight into the possible pathogenesis involved in the FD phenotype and enhances the understanding of its molecular signaling pathways, offering theoretical evidence for the feasibility of potential therapeutic targets for FD.
摘要:
纤维发育不良(FD)是由鸟嘌呤核苷酸结合蛋白突变引起的骨骼干细胞疾病,α-刺激活性多肽(GNAS)基因,这导致环磷酸腺苷(cAMP)的异常积累和下游信号通路的过度激活。甲状旁腺激素相关蛋白(PTHrP)由成骨细胞谱系分泌,参与骨骼的各种生理和病理活动。然而,PTHrP异常表达与FD,以及它的潜在机制,尚不清楚。在这项研究中,我们发现,与正常对照患者来源的骨髓基质细胞(NCBMSCs)相比,FD患者来源的骨髓基质细胞(FDBMSCs)在成骨分化过程中表达显著较高水平的PTHrP,并表现出更高的增殖能力,但成骨能力受损.在体外和体内实验中,NCBMSCs的持续外源PTHrP暴露均促进了FD表型。通过PTHrP/cAMP/PKA轴,PTHrP可通过过度激活Wnt/β-Catenin信号通路部分影响FDBMSCs的增殖和成骨能力。此外,PTHrP不仅直接调节cAMP/PKA/CREB转导,而且还被证明是CREB的转录靶标。这项研究提供了有关FD表型的可能发病机制的新见解,并增强了对其分子信号通路的理解。为FD潜在治疗靶点的可行性提供理论证据。