Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Drug Treatment, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
Sci Rep. 2024 Jun 5;14(1):12967. doi: 10.1038/s41598-024-63439-4.
Osteoporosis is a common skeletal disease affecting millions of individuals world-wide, with an increased risk of fracture, and a decreased quality of life. Despite its well-known consequences, the etiology of osteoporosis and optimal treatment methods are not fully understood. Human genetic studies have identified genetic variants within the FMN2/GREM2 locus to be associated with trabecular volumetric bone mineral density (vBMD) and vertebral and forearm fractures, but not with cortical bone parameters. GREM2 is a bone morphogenetic protein (BMP) antagonist. In this study, we employed Grem2-deficient mice to investigate whether GREM2 serves as the plausible causal gene for the fracture signal at the FMN2/GREM2 locus. We observed that Grem2 is moderately expressed in bone tissue and particularly in osteoblasts. Complete Grem2 gene deletion impacted mouse survival and body growth. Partial Grem2 inactivation in Grem2 female mice led to increased trabecular BMD of femur and increased trabecular bone mass in tibia due to increased trabecular thickness, with an unchanged cortical thickness, as compared with wildtype littermates. Furthermore, Grem2 inactivation stimulated osteoblast differentiation, as evidenced by higher alkaline phosphatase (Alp), osteocalcin (Bglap), and osterix (Sp7) mRNA expression after BMP-2 stimulation in calvarial osteoblasts and osteoblasts from the long bones of Grem2 mice compared to wildtype littermates. These findings suggest that GREM2 is a possible target for novel osteoporotic treatments, to increase trabecular bone mass and prevent osteoporotic fractures.
骨质疏松症是一种常见的骨骼疾病，影响着全球数以百万计的人，增加了骨折的风险，并降低了生活质量。尽管其后果众所周知，但骨质疏松症的病因和最佳治疗方法尚未完全了解。人类遗传研究已经确定 FMN2/GREM2 基因座内的遗传变异与小梁体积骨矿物质密度（vBMD）和椎体及前臂骨折有关，但与皮质骨参数无关。GREM2 是一种骨形态发生蛋白（BMP）拮抗剂。在这项研究中，我们使用 Grem2 缺陷小鼠来研究 GREM2 是否是 FMN2/GREM2 基因座骨折信号的可能因果基因。我们观察到 Grem2 在骨组织中中度表达，特别是在成骨细胞中。完全缺失 Grem2 基因会影响小鼠的存活和生长。Grem2 杂合子雌性小鼠中部分 Grem2 失活导致股骨小梁 BMD 增加，胫骨小梁骨量增加，这是由于小梁厚度增加，而皮质厚度不变，与野生型同窝仔鼠相比。此外，Grem2 失活刺激成骨细胞分化，这可以通过颅骨成骨细胞和 Grem2 小鼠长骨成骨细胞中碱性磷酸酶（Alp）、骨钙素（Bglap）和骨形成蛋白 2（BMP-2）刺激后的骨桥蛋白（Sp7）mRNA 表达升高来证明。这些发现表明，GREM2 可能是治疗骨质疏松症的新靶点，以增加小梁骨量并预防骨质疏松性骨折。
