Biology subjects

Motyl, K. J.

Publications and source records attributed to Motyl, K. J..

6 recordsLinked to original sources

bioRxiv2026

Short- and Long-Term Effects of Social Isolation on Adult Murine Bone are Sex-Dependent

Social isolation is a known modifiable risk factor for many chronic diseases including cardiovascular, metabolic, and neurological disorders. Recent research has demonstrated that social isolation is similarly detrimental to skeletal health, but these effects may be sexually dimorphic. In rodents, isolation negatively affects bone in adult male mice, but not in females. However, these sex differences have not been systematically investigated, and it is unknown if they persist with long-term social isolation. The goal of our study was to investigate if isolation-induced bone loss may occur on different timescales between female and male mice, as well as investigate the potential roles of estrogen and testosterone. We examined bone changes in grouped (4 mice/cage) or isolated (1 mouse/cage) female and male 16-week-old C57BL/6J mice after 2, 4, or 8 weeks of treatment. We found that social isolation through single housing significantly reduced bone parameters across treatment lengths in male mice (20% average reduction in Tb.BV/TV; 8% average reduction in Ct.Th.) but not in females even with prolonged isolation. In trabecular bone, isolation affected male bone parameters in as little as 2 weeks. Isolation also decreased biomechanical properties in the femur of male but not female mice. While the females overall bone phenotype was unaffected, isolated females did show an increase in bone turnover markers with 2 weeks of isolation. Isolation also altered estrogen-related gene expression in male mice isolated for 4 or 8 weeks. Overall, our results demonstrate that both short- and long-term social isolation has sexually dimorphic effects on murine bone. These findings have important clinical implications for individuals at risk for social isolation, as well as for pre-clinical rodent models utilizing single housing. Lay SummarySocial isolation may have worse effects on bone in males than females, but this has not been thoroughly explored. We investigated if different lengths of isolation had different effects on the bones of male and female mice. We found that both short- and long-term isolation had a rapid and negative impact on the bones of male but not female mice, although isolated females did show some changes in markers of bone formation and resorption. These findings have important implications for humans at risk for social isolation, as well as for studies with rodents that use single housing.

physiology↗

bioRxiv2025

A synbiotic medical food improves gut barrier function, reduces immune responses, and inhibits osteoclast activity in models of postmenopausal bone loss aligned with clinical outcomes

Over half of women above age 50 are affected by osteopenia or osteoporosis, boneloss conditions influenced by estrogen decline, inflammation, and the intestinal microbiota. Probiotic-based interventions have shown promise in preclinical osteoporosis models. In a recent randomized, double-blind, placebo-controlled clinical trial of postmenopausal women, dietary intervention with SBD111, a synbiotic medical food combining plant-derived probiotics and prebiotic fibers, reduced bone loss in women with osteopenia, elevated body mass index (BMI), and/or elevated body fat. To investigate potential mechanisms underlying these outcomes, we examined intestinal epithelial, immune, and osteoclast responses to SBD111 in vitro. SBD111 administration improved intestinal barrier integrity, reduced immune cell cytokine secretion, and inhibited osteoclast activity. These effects align with clinically observed reductions in severe gastrointestinal symptoms and bone resorption markers. Together, these findings suggest that SBD111 modulates the gut-bone axis via barrier, immune, and antiresorptive pathways, supporting its role in maintaining skeletal health in postmenopausal women. IRB StatementsThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of MaineHealth under protocol 1689738-1 (approved 12/29/2020) and 958914 (approved 05/31/2005). Human peripheral blood mononuclear cells (PBMCs) were purchased from Charles River Laboratories and collected under their IRB-approved protocol with informed consent for commercial research use. Informed Consent Statements Informed consent was obtained from all participants involved in the study. HighlightsO_LISBD111 synbiotic medical food improves intestinal barrier function C_LIO_LISBD111 reduces cytokine release from inflamed immune cells C_LIO_LIThis synbiotic medical food inhibits osteoclast activity in vitro C_LIO_LIIn vitro SBD111 effects align with clinical reductions in bone loss and CTX-1 C_LI Graphical Abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/669142v1_ufig1.gif" ALT="Figure 1000"> View larger version (30K): org.highwire.dtl.DTLVardef@13b16dcorg.highwire.dtl.DTLVardef@59dfcaorg.highwire.dtl.DTLVardef@737e59org.highwire.dtl.DTLVardef@6c054a_HPS_FORMAT_FIGEXP M_FIG SBD111 synbiotic medical food reduces bone loss via barrier improvement, anti-inflammation, and osteoclast inhibition. (A) SBD111 improves barrier integrity in vitro. Visualized in the left panel, inflammation reduces intestinal epithelial barrier function, resulting in the influx of inflammatory mediators, thereby activating the immune system. The addition of SBD111, shown in purple (right), improves barrier function, reducing the ability of inflammatory mediators to cross the epithelial barrier. (B) SBD111 reduces inflammatory responses of inflamed immune cells in a concentration-dependent manner. Low concentrations of SBD111 induce inflammatory responses. At higher concentrations, fewer inflammatory cytokines are secreted. (C) SBD111-derived components/metabolites inhibit the activity of bone-resorbing osteoclasts and reduce their ability to degrade bone. Image created in https://BioRender.com C_FIG

immunology↗

bioRxiv2024

Thermoneutral Housing has Limited Effects on Social Isolation-Induced Bone Loss in Male C57BL/6J Mice

Social isolation stress has numerous known negative health effects, including increased risk for cardiovascular disease, dementia, as well as overall mortality. The impacts of social isolation on skeletal health, however, have not been thoroughly investigated. We previously found that four weeks of social isolation through single housing led to a significant reduction in trabecular and cortical bone in male, but not female, mice. One possible explanation for these changes in male mice is thermal stress due to sub-thermoneutral housing. Single housing at room temperature ([~]20-25{degrees}C)--below the thermoneutral range of mice ([~]26-34{degrees}C)--may lead to cold stress, which has known negative effects on bone. Therefore, the aim of this study was to test the hypothesis that housing mice near thermoneutrality, thereby ameliorating cold-stress, will prevent social isolation-induced bone loss in male C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) at either room temperature ([~]23{degrees}C) or in a warm temperature incubator ([~]28{degrees}C) for four weeks (N=8/group). As seen in our previous studies, isolated mice at room temperature had significantly reduced bone parameters, including femoral bone volume fraction (BV/TV), bone mineral density (BMD), and cortical thickness. Contrary to our hypothesis, these negative effects on bone were not ameliorated by thermoneutral housing. Social isolation increased glucocorticoid-related gene expression in bone and Ucp1 and Pdk4 expression in BAT across temperatures, while thermoneutral housing increased percent lipid area and decreased Ucp1 and Pdk4 expression in BAT across housing conditions. Overall, our data suggest social isolation-induced bone loss is not a result of thermal stress from single housing and provides a key insight into the mechanism mediating the effects of isolation on skeletal health. Lay SummarySocial isolation is a major public health concern and is known to increase the risk for many diseases, including heart disease and dementia. The impact of social isolation on bone health, however, has not been well-studied. We previously found that four weeks of social isolation reduces bone in male mice. Isolated mice may experience more cold stress than mice housed in groups, as we commonly keep laboratory mice at temperatures below their ideal range, which could lead to bone loss. The aim of our study was therefore to test if housing mice at warmer temperatures, within their ideal temperature range, prevents isolation-induced bone loss in male mice. We found that housing mice at warmer temperatures did not fully prevent isolation-induced bone loss. We also found social isolation increased the expression of genes related to glucocorticoid signaling in bone across temperatures, as well as genes associated with mitochondrial metabolism within fat tissue. Overall, our results show that social isolation-induced bone loss is likely not a result of cold stress from single housing and provide insight into the mechanisms by which isolation causes bone loss.

physiology↗

bioRxiv2023

Social Isolation Causes Cortical and Trabecular Bone Loss in Adult Male, but not Female, C57BL/6J Mice

Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and loneliness, researchers have been concerned about a rising "epidemic" of loneliness. Isolation is associated with an increased risk for many physical and mental health disorders and increased overall mortality risk. In addition to social isolation, older adults are also at greater risk for osteoporosis and related fractures. While researchers have investigated the negative effects of other forms of psychosocial stress on bone, including depression and PTSD, the effects of social isolation on bone have not been thoroughly investigated. The aim of this study was to test the hypothesis that social isolation would lead to bone loss in male and female C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) for four weeks (N=16/group). Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI, Ct.Por.) parameters in male, but not female mice. Isolated male mice had signs of reduced bone remodeling represented by reduced osteoblast numbers, osteoblast-related gene expression and osteoclast-related gene expression. However, isolated females had increased bone resorption-related gene expression, without any change in bone mass. Overall, our data suggest that social isolation has negative effects on bone in males, but not females, although females showed suggestive effects on bone resorption. These results provide critical insight into the effects of isolation on bone and have key clinical implications as we grapple with the long-term health impacts of the rise in social isolation related to the COVID-19 pandemic.

physiology↗

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↗