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

Topic: Inflammation, microglia and astrocytes

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).

Key findings

• 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.
• 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.

New to this subject? Start with our plain-English guide: Genetics →

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1002/jbmr.4572
• PubMed: 35575023
• Original source →

Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.

@article{essex2022-35575023,
  author  = {Essex, Alyson L and Huot, Joshua R and Deosthale, Padmini and Wagner, Alison and Figueras, Jorge and Davis, Azaria and Damrath, John and Pin, Fabrizio and others},
  title   = {{Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) R47H Variant Causes Distinct Age- and Sex-Dependent Musculoskeletal Alterations in Mice}},
  journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research},
  year    = {2022},
  doi     = {10.1002/jbmr.4572},
  pmid    = {35575023},
  url     = {https://doi.org/10.1002/jbmr.4572}
}

Related studies in TREM2 and immune genetics

• The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles Brain communications · 2021-02-03 · usefulness score 45/100
• Triggering receptor expressed on myeloid cells 2 (TREM2) dependent microglial activation promotes cisplatin-induced peripheral neuropathy in mice Brain, behavior, and immunity · 2017-10-16 · usefulness score 40/100
• Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015-01-15 · usefulness score 38/100
• Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke PloS one · 2013-01-03 · usefulness score 47/100
• Investigation of triggering receptor expressed on myeloid cells 2 variant in the Wisconsin Registry for Alzheimer's Prevention Neurobiology of aging · 2013-11-20 · usefulness score 64/100
• Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease Neurobiology of aging · 2013-04-09 · usefulness score 52/100

Also tagged “expressed”

384 studies in the library carry the topic tag “expressed”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 384 tagged studies.

• Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system Glia · 2002-11-01 · usefulness score 36/100 · Brain scans and imaging
• Brain-wide microglia replacement using a nonconditioning strategy ameliorates pathology in mouse models of neurological disorders Science translational medicine · 2025-04-30 · usefulness score 43/100 · TREM2 and immune genetics
• Genetic Risk Factors for Alzheimer Disease: Emerging Roles of Microglia in Disease Pathomechanisms Advances in experimental medicine and biology · 2019 · usefulness score 39/100 · Genetics

Similar studies

• The Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) as Expression of the Relationship between Microglia and Alzheimer's Disease: A Novel Marker for a Promising Pathway to Explore 2019 · TREM2 and immune genetics
• Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone 2026 · Genetics
• Microglial TREM2 at the Intersection of Brain Aging and Alzheimer's Disease 2023 · TREM2 and immune genetics
• The role of TREM2 in Alzheimer's disease; evidence from transgenic mouse models 2020 · TREM2 and immune genetics
• TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer's Disease: Lessons Learned from Transcriptomics 2021 · TREM2 and immune genetics
• TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice 2017 · TREM2 and immune genetics

More on TREM2 and immune genetics

• A review that covers this ground Differential role of triggering receptors expressed on myeloid cells 2 R47H in 3 neurodegenerative diseases based on a systematic review and meta-analysis Medicine · 2020-01-01 · usefulness score 58/100
• Newest in this subject Soluble TREM2 suppresses neuronal activity Research Square · 2026-10-28 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject NADPH attenuates tau pathology and disease-associated microglial phenotype in a truncated tau- induced mouse model Research Square · 2026-10-19 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in TREM2 and immune genetics →