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

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.