TREM2 Gene Variant Reshapes Bone Structure Differently in Male and Female Mice

A gene variant best known for its links to neurodegenerative disease has now been shown to leave a measurable imprint on the skeleton, and the imprint depends on which sex chromosomes a mouse carries and which gonads it has. In a study published in Biology of Sex Differences, researchers examined mice carrying the R47H variant of the Triggering Receptor Expressed on Myeloid Cells 2 gene, or TREM2, and found that its effects on bone structure were moderate but clearly shaped by both chromosomal and gonadal sex. The work used the Four Core Genotypes mouse model, a system that allows scientists to separate the influence of sex chromosomes from the influence of ovaries or testes.

TREM2 is expressed in cells of the hematopoietic lineage, including microglia in the brain and osteoclasts in bone. Previous studies had shown that expression of the TREM2-R47H variant leads to an altered musculoskeletal phenotype in a sex-dependent manner, and that gonadectomy ameliorates the skeletal phenotype of gonadal female TREM2R47H/+ mice. Earlier work from the same group also indicated that sex chromosomes play a key role in skeletal mass and bone strength. Because mice expressing the variant showed sex-dimorphic bone and skeletal muscle phenotypes, the team turned to the Four Core Genotypes model to determine whether chromosomes or gonads drive the differences.

To build the experimental population, FCG C57Bl/6J mice expressing the TREM2-R47H variant were mated to obtain both TREM2 wildtype and TREM2R47H/+ mice within the four core genotype groups. The animals were analyzed at four to 5.5 months of age, with gonadal males classified as XXT and XYT and gonadal females as XXO and XYO. Body weight and bone mineral density were measured at baseline and again at the endpoint of 5.5 months using DXA with a Piximus instrument. At the endpoint, the researchers applied micro-computed tomography to map bone architecture, dynamic and static histomorphometry to quantify cellular activity, a three-point bending test to assess mechanical properties, and measurements of bone turnover markers in serum.

Statistical analysis relied on two-way ANOVA performed in Prism 10, run separately for each gonadal sex to identify the contributions of chromosome sex, the presence of the TREM2-R47H variant, and their interaction. This design meant the team could ask, for example, whether an XX chromosome complement produced different bone outcomes than an XY complement within gonadal males, and whether the variant changed those outcomes differently depending on the chromosome complement. The approach is one of the most direct ways to disentangle hormonal from chromosomal contributions to a biological trait, because it holds gonadal type constant while varying chromosomes, and vice versa.

In gonadal males, the results pointed to a substantial chromosomal component. Chromosome sex effects appeared for several bone structural parameters in the femur and the fifth lumbar vertebra as assessed by micro-computed tomography. In addition, there was an interaction between gonadal sex and chromosome sex for other structural measurements in both bones, which the authors interpreted as evidence that the effect of the TREM2 variant depends on the presence of the Y chromosome in gonadal males. Mechanical testing reinforced the chromosomal signal, showing chromosome sex effects with higher overall values for XXT mice regardless of whether the TREM2 variant was present.

At the cellular level in gonadal males, chromosome sex influenced osteoblast number and surface, but not osteoclast parameters, and it did so similarly for wildtype and TREM2 mutant animals. Bone formation on the femur cortex and serum markers of formation and resorption were unchanged, suggesting that the structural differences observed at 5.5 months result from bone modeling or remodeling that occurred at an earlier age rather than from ongoing changes in adult bone turnover. This timing distinction matters for interpretation, because it implies the variant and chromosome effects may be baked into the skeleton during growth rather than continuously modulating it in adulthood.

Gonadal females showed a different and in some respects richer pattern of effects. Chromosome sex affected body weight gain, which was higher in XYO than in XXO mice, but it did not affect bone mineral density accrual. Chromosome sex also affected the percent change in total lean mass between initial and final measurements, again with XYO exceeding XXO, and there was a chromosome sex by TREM2 genotype interaction along with differences in total and percent fat mass, which were lower in TREM2R47H/+ than wildtype mice, and percent lean mass, which was higher in the mutant, but only for XYO mice. These body composition findings indicate that the variant’s systemic effects in gonadal females are restricted to the XY chromosome complement.

Skeletal outcomes in gonadal females followed a site-specific logic. Chromosome sex affected distal femur volumetric bone mass, with XYO higher than XXO, while the TREM2 genotype influenced lumbar vertebra trabecular number and separation, which trended higher in TREM2R47H/+ versus wildtype mice for the sex complement. In the femur cortex, chromosome sex was the dominant factor, with overall higher values in XXO mice independent of TREM2 genotype. Mechanical testing parameters were likewise influenced by chromosome sex, with XXO exceeding XYO mice. Femur cortical bone formation was higher on the endocortical surface but lower on the periosteal surface in XXO compared with XYO mice, a chromosome sex effect. The authors suggested that these opposite effects on the two bone surfaces might explain why the serum bone formation marker, Procollagen Type 1 N-terminal propeptide, or P1NP, remained unchanged. Chromosome sex did affect the resorption marker C-terminal telopeptide of type 1 collagen, or CTX-1, which was lower in XXO than in XYO mice.

Cellular analyses in gonadal females revealed an interaction between chromosome sex and TREM2 genotype for osteoclast, but not osteoblast, parameters in vertebral trabecular bone. Osteoclast number and surface were higher in TREM2R47H/+ mice only for XYO animals, and, as with CTX-1, were lower in XXO compared with XYO mice only among the mutants. Taken together, the authors concluded that chromosome sex partially affects the consequences of TREM2-R47H expression on bone structure in 5.5-month-old mice, whereas the outcomes of the gene variant depend on the gonadal sex of the animal. The findings add to previous publications from the group and suggest that the consequences of expressing the R47H variant on the musculoskeletal system depend on the presence of sex hormones and chromosome sex in a manner that varies by bone site or skeletal muscle studied. The authors noted that future studies will determine whether the cellular changes observed here, in both cell number and activity, produce a stronger bone phenotype at an older age.

Subject of Research: How the TREM2-R47H gene variant affects bone structure in mice depending on chromosomal and gonadal sex

Article Title: Moderate effects of the Arginine to Histidine R47H variant of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) on bone structure in four core genotypes gonadal male and female mice

Article References: Ramirez, G., Teal, A., Hernandez, D., Chellaganapathy, L., Pianeta, R., Segvich, D. M., Wallace, J. M., & Plotkin, L. I. (2026). Moderate effects of the Arginine to Histidine R47H variant of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) on bone structure in four core genotypes gonadal male and female mice. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-01008-2

Image Credits: AI Generated

DOI: 10.1186/s13293-026-01008-2

Keywords: TREM2, R47H variant, bone structure, Four Core Genotypes mice, chromosomal sex, gonadal sex, osteoclasts, osteoblasts, micro-computed tomography, bone remodeling, sex differences, mechanical testing