Chronic Disease Research Institute, The Children's Hospital, National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China; Department of Nutrition and Food Hygiene, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Program in Developmental & Stem Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
Bone. 2025 Jan;190:117282. doi: 10.1016/j.bone.2024.117282. Epub 2024 Oct 12.
Iroquois homeobox gene 3 (Irx3) and Irx5 encode transcription factors that play crucial roles in limb development and bone formation. Previous studies using knockout mice have revealed a role of Irx3 and Irx5 in osteogenesis in young adult mice. However, whether these genes are also essential for bone homeostasis in adulthood and contribute to bone diseases remain poorly understood. Osteoporosis is a disease characterized by lower bone mineral density and disrupted bone microarchitecture, typically occurs in postmenopausal women. Here, we demonstrate that Irx3/5 mice with a half-reduction of Irx3 and Irx5 dosage serve as a novel model of osteoporosis. By micro-computed tomography, we found that Irx3/5 mice exhibited sex-dependent bone loss patterns. While male Irx3/5 mice progressively lost trabecular microstructures with aging, female mutants exhibited lower bone mineral density (BMD) and bone volume fraction (BV/TV) at early adulthood (9-15 weeks old) but without further loss later at 1 year of age. Bone marrow adipocytes are known to be elevated at the expenses of lower osteogenesis in osteoporotic bone marrow. Surprisingly, we found sex-dependent changes in adipogenesis at the age of skeletal maturity that bone marrow adipocytes were reduced in female Irx3/5 mice along with deteriorated osteogenesis, while male mice exhibited elevated adipogenesis. In summary, we reported a novel genetic model for osteoporosis-like phenotypes, highlighting sex-dependent bone mineral density and bone marrow adipocyte characteristics.
伊洛奎斯同源框基因 3 (Irx3) 和 Irx5 编码转录因子，在肢体发育和骨骼形成中发挥着关键作用。使用基因敲除小鼠的先前研究揭示了 Irx3 和 Irx5 在年轻成年小鼠成骨中的作用。然而，这些基因是否对成年期的骨骼稳态也至关重要，并导致骨骼疾病，仍知之甚少。骨质疏松症是一种以骨矿物质密度降低和骨微观结构破坏为特征的疾病，通常发生在绝经后妇女中。在这里，我们证明 Irx3/5 小鼠 Irx3 和 Irx5 剂量减少一半可作为骨质疏松症的新型模型。通过微计算机断层扫描，我们发现 Irx3/5 小鼠表现出性别依赖性的骨丢失模式。虽然雄性 Irx3/5 小鼠随着年龄的增长逐渐失去了小梁微观结构，但雌性突变体在成年早期（9-15 周龄）表现出较低的骨矿物质密度（BMD）和骨体积分数（BV/TV），但在 1 岁时没有进一步丢失。已知骨质疏松症骨髓中的骨髓脂肪细胞会增加，而成骨作用会降低。令人惊讶的是，我们在骨骼成熟时发现了脂肪生成的性别依赖性变化，即雌性 Irx3/5 小鼠的骨髓脂肪细胞减少，同时成骨作用恶化，而雄性小鼠则表现出脂肪生成增加。总之，我们报道了一种骨质疏松样表型的新型遗传模型，突出了性别依赖性的骨矿物质密度和骨髓脂肪细胞特征。
