Wu Di, Cline-Smith Anna, Goering Daniel, Choudhary Aarushi, Veis Deborah, Aurora Rajeev
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63104.
J Bone Miner Res. 2025 Jun 28. doi: 10.1093/jbmr/zjaf089.
Fragility fractures are a significant cause of morbidity and mortality in postmenopausal women. Menopause leads to a significant decline in bone mass and quality, with over half of women sustaining fragility fractures without reaching the osteoporotic threshold (T-score < -2.5), underscoring the pivotal role of bone quality in fracture risk. Previous studies have shown that estrogen (E₂) deficiency following ovariectomy (OVX) in mice activates memory T-cells (TM) to produce TNFα and IL-17A, resulting in trabecular bone loss. This study extends these findings to cortical bone, revealing that under habitual load osteoclasts are predominantly localized on the posterior endosteal surface. Post-OVX, mice exhibited enlarged lacunae indicative of osteocytic osteolysis and reduced dendrite density in osteocytes (Ocy) adjacent to T-cells, with these effects being more pronounced on the posterior side where osteoclast-T-cell interactions are heightened. Additionally, osteoblast (OB) function analysis revealed that while bone formation at the mid-diaphysis remained unchanged, the collagen matrix became more disorganized, particularly in the posterior cortical compartment. Importantly, OVX increased bone fragility without altering cortical thickness or mineral density. These detrimental changes were absent in OVX mice lacking TNFα and IL-17A expression in TM cells (IL15RAΔT), suggesting that these cytokines specifically impair the osteolineage (Ocy and OB), compromising bone quality in ways undetectable by μCT. Our findings reveal a novel mechanism where T-cell-mediated inflammation reduced cortical bone quality by targeting the osteolineage, leading to disrupted matrix organization and Ocy dendrite density. Clinically, these results highlight the potential of targeting T-cell responses to maintain bone quality and strength in estrogen-deficient states. Additionally, estrogen loss adversely affects endosteal bone quality in distinct cortical compartments without impacting bone mass, a deficit that may remain undetected by DXA scans.
脆性骨折是绝经后女性发病和死亡的重要原因。绝经导致骨量和骨质量显著下降，超过半数的女性在未达到骨质疏松阈值（T值＜-2.5）时就发生了脆性骨折，这突出了骨质量在骨折风险中的关键作用。先前的研究表明，小鼠卵巢切除（OVX）后雌激素（E₂）缺乏会激活记忆T细胞（TM）产生TNFα和IL-17A，导致小梁骨丢失。本研究将这些发现扩展至皮质骨，揭示了在习惯性负荷下破骨细胞主要位于骨内膜后端表面。OVX后，小鼠出现骨陷窝扩大，提示骨细胞性骨溶解，且与T细胞相邻的骨细胞（Ocy）中树突密度降低，这些效应在破骨细胞与T细胞相互作用增强的后侧更为明显。此外，成骨细胞（OB）功能分析显示，虽然骨干中部的骨形成保持不变，但胶原基质变得更加紊乱，尤其是在皮质骨后侧区域。重要的是，OVX增加了骨脆性，但未改变皮质厚度或矿物质密度。在TM细胞中缺乏TNFα和IL-17A表达的OVX小鼠（IL15RAΔT）中未出现这些有害变化，这表明这些细胞因子特异性损害骨谱系（Ocy和OB），以μCT无法检测到的方式损害骨质量。我们的研究结果揭示了一种新机制，即T细胞介导的炎症通过靶向骨谱系降低皮质骨质量，导致基质组织破坏和Ocy树突密度降低。临床上，这些结果突出了针对T细胞反应以在雌激素缺乏状态下维持骨质量和强度的潜力。此外，雌激素丧失对不同皮质区域的骨内膜骨质量产生不利影响，而不影响骨量，这种不足可能无法通过双能X线吸收法（DXA）扫描检测到。
