Contribution of chromosome versus gonadal sex to bone mass and strength

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SUMMARY Alzheimer's disease (AD) is a growing health concern and is the most common type of dementia worldwide, affecting women with higher frequency. Evidence indicates that mental illness and neurological and nervous system disorders can increase the risk of developing osteoporosis leading to high prevalence of bone frac- tures. Fractures, in particular of the hip, have been associated with increased mortality, especially in the elder- ly. Conversely, osteoporosis is associated with higher risk of dementia diagnosis. Yet, a direct link between dementia and osteoporosis, frequently occurring with aging, has never been conclusively demonstrated. Inter- estingly, some genetic mutations are risk factors for both AD and osteoporosis. For example, mutations of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a molecule expressed in microglia in brain and in osteoclasts in bone correlate with AD and dementia, and with bone fragility. Recent studies showed that mice expressing the TREM2 R47H variant (TREM2R47H/+ mice) exhibit loss of TREM2 function and neuritic dystro- phy. However, the mechanisms responsible for the TREM2 mutation effects on bone mass and strength are completely unclear. We have shown that females TREM2R47H/+ mice exhibit low bone mass accrual compared to wild type littermates, whereas no changes were observed in males. In addition, female, but not male, TREM2R47H/+ mice exhibit low total and femur BMD at 5.5, but not at 4 months of age, compared to wild type littermates. Yet, the mechanism by which aging has a stronger effect in female TREM2R47H/+ compared wild type mice is not known. Our long-term goal is to understand the basis for bone sexual dimorphism. The ob- jective of this supplement is to extend the original studies funded by the R21 award to a model of increased risk of developing AD, with the aim to start uncovering the mechanisms for the increase susceptibility to devel- oping AD in females. We propose to test the hypothesis that the differential skeletal consequences of ex- pression of the TREM2 R47H variant result from a combination of gonadal and chromosome sex- dependent mechanisms. To address this hypothesis, we aim to determine the contribution of gonadal versus chromosome sex to bone mass and strength in 5.5-month-old wild type and TREM2R47H/+ mice. Two Sub Aims are proposed. In Sub Aim a, we will examine the skeletal consequences of the TREM2 variant in male and female mice and the role of chromosomal and gonadal sex at the structural, cellular, and molecu- lar levels in wild type and TREM2R47H/+ XXM, XYM, XXF and XYF mice. In Sub Aim b, we will identify the cellular mechanism that underly the sexual dimorphism in wild type and TREM2R47H/+ mice, by determining whether osteoclasts from TREM2R47H/+ XXM, XYM, XXF and XYF mice are intrinsically different or respond to sex steroids differently, and whether the pattern of osteoclastokines differs in a sex-dependent manner. These studies will advance our knowledge of the mechanisms controlling bone cell function in a sex-dependent manner in the context of increased risk to develop AD.