Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) R47H Variant Causes Distinct Age‐ and Sex‐Dependent Musculoskeletal Alterations in Mice

Previous studies proposed the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a receptor expressed in myeloid cells including microglia in brain and osteoclasts in bone, as a link between brain and bone disease. The TREM2 R47H variant is a known risk factor for Alzheimer's disease (AD), the most common form of dementia. To investigate whether altered TREM2 signaling could contribute to bone and skeletal muscle loss, independently of central nervous system defects, we used mice globally hemizygous for the TREM2 R47H variant (TREM2(R47H/+)), which do not exhibit AD pathology, and wild‐type (WT) littermate control mice. Dxa/Piximus showed bone loss in female TREM2(R47H/+) animals between 4 and 13 months of age and reduced cancellous and cortical bone (measured by micro‐computed tomography [μCT]) at 13 months, which stalled out by 20 months of age. In addition, they exhibited decreased femoral biomechanical properties measured by three‐point bending at 13 months of age, but not at 4 or 20 months. Male TREM2(R47H/+) animals had decreased trabecular bone geometry but increased ultimate strain and failure force at 20 months of age versus WT. Only male TREM2(R47H/+) osteoclasts differentiated more ex vivo after 7 days with receptor activator of nuclear factor κB ligand (RANKL)/macrophage colony‐stimulating factor (M‐CSF) compared to WT littermates. Yet, estrogen receptor alpha expression was higher in female and male TREM2(R47H/+) osteoclasts compared to WT mice. However, female TREM2(R47H/+) osteoclasts expressed less complement 3 (C3), an estrogen responsive element, and increased protein kinase B (Akt) activity, suggesting altered estrogen signaling in TREM2(R47H/+) cells. Despite lower bone volume/strength in TREM2(R47H/+) mice, skeletal muscle function measured by plantar flexion and muscle contractility was increased in 13‐month‐old female mutant mice. Overall, these data demonstrate that an AD‐associated TREM2 variant can alter bone and skeletal muscle strength in a sex‐dimorphic manner independent of central neuropathology, potentially mediated through changes in osteoclastic intracellular signaling. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).