Estrogen Loss Activates Memory T-Cells to Compromise Bone Integrity Through Distinct Cortical Compartments in Mice.

IF 5.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Di Wu, Anna Cline-Smith, Daniel Goering, Aarushi Choudhary, Deborah Veis, Rajeev Aurora
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引用次数: 0

Abstract

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.

雌激素缺失激活记忆t细胞,通过小鼠不同的皮质区室损害骨完整性。
脆性骨折是绝经后妇女发病和死亡的重要原因。绝经期导致骨量和质量显著下降,超过一半的女性在未达到骨质疏松阈值(t评分)的情况下持续脆性骨折
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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
期刊介绍: The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.
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