Biology subjects

Bouxsein, M.

Publications and source records attributed to Bouxsein, M..

4 recordsLinked to original sources

bioRxiv2026

Comparison of lumbar paraspinal muscle size and density between members of the US Framingham Heart Study and Tsimane forager-horticulturalists of Bolivia

Paraspinal muscles support and move the spine, and reduced size and density of these muscles is associated with increased risk of vertebral fracture and back pain. We test the hypothesis that subsistence-oriented forager-horticulturalists (Bolivian Tsimane) have larger and denser paraspinal muscles, and smaller age-related differences in paraspinal muscle size and density, than more sedentary post-industrialized suburbanites (Framingham Heart Study [FHS]). We measured cross-sectional area (CSA) and density of trunk extensors and psoas major at L3 from computed tomography scans of 411 FHS and 330 Tsimane (50% women, aged 50-90 years). Sex-stratified linear regressions determined associations of muscle CSA and density with age and cohort (Tsimane or FHS [ref.]), with and without an age-cohort interaction term. Covariates were height and weight. After adjusting for covariates, Tsimane women had 11-14% larger and denser extensors, and 17-26% smaller and less-dense psoas major, than FHS women. Tsimane men had 8-21% smaller and less-dense psoas major than FHS men. The age-related difference in extensors density was 41% smaller for Tsimane men than for FHS men. There were no other significant age-related cohort differences in muscle CSA or density. We observed a different balance in the size and density of trunk extensors versus psoas major between Tsimane and FHS. A possible explanation for this observation is cohort differences in the amount and types of physical activity, although future work is required to determine the influence of lifestyle and environmental factors on paraspinal muscle size and density.

evolutionary biology↗

bioRxiv2026

Deletion of Dock7 Exons 3 and 4 Results in Reduced Trabecular Microarchitecture and a Decrease in Mineralization

Dedicator of Cytokinesis 7 (DOCK7) has recently emerged as a regulator of skeletal homeostasis, but existing Dock7 mutant models harbor only global mutations and are incompatible with tissue-specific deletion studies. We previously generated a Dock7-floxed allele in which exons 3-4 are flanked by LoxP sites. To validate the utility of this allele for future conditional strategies, we globally deleted exons 3-4 to generate Dock7em2/em2 mice and characterized their skeletal phenotype. Homozygous Dock7em2/em2 mice exhibited a diluted coat color and white belly spot, consistent with spontaneous Dock7 mutations, whereas heterozygotes exhibited no spotting or coat changes. Bone microarchitecture was assessed in 21-week-old males and females. Global deletion of Dock7 exons 3-4 resulted in a 30-37% reduction in trabecular bone volume in the distal femur and L5 vertebrae. Cortical bone thickness was unchanged, though sex-specific alterations in femoral area suggested altered appositional bone growth. Mass spectrometry (SWATH) analysis of Dock7em2/em2 bone marrow stromal cells (BMSCs) identified DOCK7 protein levels similar to control mice, likely resulting from an alternative translational start site. Despite stable protein abundance prior to differentiation, BMSCs from Dock7em2/em2 mice exhibited reduced mineralization and decreased Bglap expression, indicating attenuated osteoblast differentiation. These findings demonstrate that Dock7 exons 3-4 are required for normal trabecular bone acquisition and osteoblast function. While the Dock7-em2 allele likely encodes a truncated protein product, its recapitulation of the Misty skeletal phenotype confirms that exons 3-4 are essential for DOCK7 activity. These studies in the Dock7em2/em2 mouse provide a foundation for future tissue-specific deletion studies utilizing the Dock7 exon 3-4 deletion model to define the cellular roles of DOCK7 in regulating bone formation and trabecular architecture. Lay SummaryIdentifying genes that regulate bone mass is essential for understanding osteoporosis. Mutation of the Dock7 gene in mice results in low bone mass, similar to human osteoporosis. Previous models could not isolate its role in specific tissues, limiting our ability to understand how DOCK7 controls bone mass. We developed a new mouse model where Dock7 can be mutated in specific tissues. In this study, we bred mice to carry this mutation across all tissues, causing significant bone loss. This validates a flexible tool for future research to mutate DOCK7 in specific cell types and map its role in skeletal health.

cell biology↗

bioRxiv2022

Sustained morphine delivery suppresses bone formation and alters metabolic and circulating miRNA profiles in male C57BL/6J mice

Opioid use is detrimental to bone health, causing both indirect and direct effects on bone turnover. While the mechanisms of these effects are not entirely clear, recent studies have linked chronic opioid use to alterations in circulating miRNAs. Our aim was to develop a model of opioid-induced bone loss to understand bone turnover and identify candidate miRNA-mediated regulatory mechanisms. We evaluated the effects of sustained morphine treatment on the skeleton, metabolism, and body composition of male and female C57BL/6J mice by treating with vehicle (0.9% saline) or morphine (18 mg/kg) using subcutaneous osmotic minipumps for 25 days. Morphine-treated mice had higher energy expenditure and respiratory quotient, indicating a shift toward carbohydrate metabolism. Microcomputed tomography ({micro}CT) analysis indicated that male mice treated with morphine had reduced trabecular bone volume fraction (Tb.BV/TV) (15%) and Tb. bone mineral density (BMD) (14%) in the distal femur compared to vehicle. Conversely, bone microarchitecture was not changed in females after morphine treatment. Histomorphometric analysis demonstrated that in males, morphine reduced bone formation rate compared to vehicle, but osteoclast parameters were not different. Furthermore, morphine reduced bone formation marker gene expression in the tibia of males (Bglap and Dmp1). Circulating miRNA profile changes were evident in males, with 14 differentially expressed miRNAs associated with morphine treatment. Target analysis indicated hypoxia inducible factor (HIF) signaling pathway was targeted by miR-223-3p and fatty acid metabolism by miR-484, - 223-3p, and -328-3p. In summary, we have established a model where morphine leads to a lower trabecular bone formation in males. Further, understanding the mechanisms of bone loss from opioid treatment will be important for improving management of the adverse effects of opioids on the skeleton.

physiology↗

bioRxiv2020

Propranolol and parathyroid hormone synergistically improve bone volume fraction by suppressing resorption

Although the non-selective {beta}-blocker, propranolol, improves bone density with PTH treatment in mice, the mechanism of this effect is unclear. To address this, we used a combination of in vitro and in vivo approaches to address how propranolol influences bone remodeling in the context of PTH treatment. In female C57BL/6J mice, intermittent PTH and propranolol had complementary effects in the trabecular bone of the distal femur and L5 vertebra, with combination treatment achieving micro-architectural parameters beyond that of PTH alone. Combined treatment improved the serum bone formation marker, P1NP, but did not impact other histomorphometric parameters relating to osteoblast function at the L5. In vitro, propranolol amplified the acute, PTH-induced, intracellular calcium signal in osteoblast-like cells. The most striking finding, however, was suppression of PTH-induced bone resorption. Despite this, PTH-induced receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA and protein levels were unaltered by propranolol, which led us to hypothesize that propranolol could act directly on osteoclasts. Using in situ methods, we found Adrb2 expression in osteoclasts in vivo, suggesting {beta}-blockers may directly impact osteoclasts. Taken together, this work suggests a strong anti-osteoclastic effect of non-selective {beta}-blockers in vivo, indicating that combining propranolol with PTH could be beneficial to patients with extremely low bone density.

physiology↗