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

Abstract

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 (TREM2R47H/+), which do not exhibit AD pathology, and wild‐type (WT) littermate control mice. Dxa/Piximus showed bone loss in female TREM2R47H/+ 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 TREM2R47H/+ animals had decreased trabecular bone geometry but increased ultimate strain and failure force at 20 months of age versus WT. Only male TREM2R47H/+ 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 TREM2R47H/+ osteoclasts compared to WT mice. However, female TREM2R47H/+ osteoclasts expressed less complement 3 (C3), an estrogen responsive element, and increased protein kinase B (Akt) activity, suggesting altered estrogen signaling in TREM2R47H/+ cells. Despite lower bone volume/strength in TREM2R47H/+ 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).

Deletion of FNDC5/Irisin modifies murine osteocyte function in a sex-specific manner

“…In vivo plantarflexion torque was assessed one day before sacrifice (Scientific Inc, Canada) as described in Pin et al (2022) . Briefly, the mouse was placed under anesthesia and the left hind foot was affixed to the force transducer aligned with the tibia at 90 ○ .…”

“…Kennewick, WA, USA) as described in Huot et al (2022) . Briefly, peak-to-peak and baseline-to-peak compound muscle action potentials (CMAP) were measured using supramaximal stimulations of <10 mA continuous current for 0.1 ms duration, and peak-to-peak single motor unit (SMUP) potentials were measured using an incremental stimulation technique.…”

“…The right femurs from mice were dissected and cleaned of soft tissue, fixed in 4% paraformaldehyde (PFA) for 48 hours, and then transferred to 70% ethanol. Ex vivo DXA measurements were obtained using a faxitron (Faxitron X-ray Corp, Wheeling, IL) to measure bone mineral density (BMD) and bone mineral content (BMC) Essex et al (2022) .…”

Alzheimer’s Disease and Impaired Bone Microarchitecture, Regeneration and Potential Genetic Links

“…A recent study demonstrated hemizygous for the TREM2 R47H variant (TREM2R47H/+) that does not exhibit AD pathology, and showed significant bone loss. Importantly, the bone phenotype was independent of brain phenotypes, indicating that TREM2 is also a genetic risk factor for osteoporosis [ 99 ]. Siglec-3 is a transmembrane sialic acid-binding receptor on the surface of microglial cells.…”

The protective activity of genistein against bone and cartilage diseases

“…However, unlike estrogen, genistein prefers to interact with ERβ (a relative binding affinity of 87% of 17β-estradiol) over ERα (4% of 17β-estradiol) in a solid-phase competitive experiment ( Kuiper et al, 1998 ). Interestingly, estrogen play a critical role in the homeostasis of musculoskeletal system ( Essex et al, 2022 ). In this article, we mainly discuss the potential roles of genistein in the protection against bone and cartilage diseases.…”