RESUMEN
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°C)-below the thermoneutral range of mice (~26-34°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°C) or in a warm temperature incubator (~28°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.
RESUMEN
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.
RESUMEN
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. Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI) 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 male, but not female mice, 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.
Asunto(s)
Resorción Ósea , COVID-19 , Femenino , Masculino , Ratones , Humanos , Animales , Ratones Endogámicos C57BL , Vivienda , Pandemias , Densidad Ósea , Hueso Cortical , Aislamiento SocialRESUMEN
Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28-30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (-13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone.
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Antipsicóticos , Femenino , Ratones , Animales , Olanzapina/efectos adversos , Antipsicóticos/efectos adversos , Vivienda , Hueso Esponjoso , Ratones Endogámicos C57BLRESUMEN
Opioid use is detrimental to bone health, causing both indirect and direct effects on bone turnover. Although the mechanisms of these effects are not entirely clear, recent studies have linked chronic opioid use to alterations in circulating miRNAs. Here, we developed 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 male and female C57BL/6J mice by treating with vehicle (0.9% saline) or morphine (17 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. Micro-computed tomography (µCT) analysis indicated a sex difference in the bone outcome, where male mice treated with morphine had reduced trabecular bone volume fraction (Tb.BV/TV) (15%) and trabecular bone mineral density (BMD) (14%) in the distal femur compared with vehicle. Conversely, bone microarchitecture was not changed in females after morphine treatment. Histomorphometric analysis demonstrated that in males, morphine reduced bone formation rate compared with 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 compared with two differentially expressed miRNAs in females. In males, 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. Consequently, expression of miR-223-3p targets, including Igf1r and Stat3, was lower in morphine-treated bone. In summary, we have established a model where morphine leads to a lower trabecular bone formation in males and identified potential mediating miRNAs. Understanding the sex-specific mechanisms of bone loss from opioids will be important for improving management of the adverse effects of opioids on the skeleton. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Enfermedades Óseas Metabólicas , MicroARN Circulante , MicroARNs , Femenino , Masculino , Ratones , Animales , Osteogénesis , Ratones Endogámicos C57BL , Microtomografía por Rayos X , Morfina/efectos adversos , Analgésicos Opioides/efectos adversos , Densidad Ósea , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Although the nonselective ß-blocker, propranolol, improves bone density with parathyroid hormone (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 administration had complementary effects in the trabecular bone of the distal femur and fifth lumbar vertebra (L5 ), with combination treatment achieving microarchitectural parameters beyond that of PTH alone. Combined treatment improved the serum bone formation marker, procollagen type 1 N propeptide (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 κ-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 ß-blockers may directly impact osteoclasts. Consistent with this, we found propranolol directly suppresses osteoclast differentiation in vitro. Taken together, this work suggests a strong anti-osteoclastic effect of nonselective ß-blockers in vivo, indicating that combining propranolol with PTH could be beneficial to patients with extremely low bone density. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Resorción Ósea , Hormona Paratiroidea , Animales , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Huesos , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Osteoblastos , Osteoclastos/metabolismo , Osteogénesis , Hormona Paratiroidea/metabolismo , Hormona Paratiroidea/farmacología , Propranolol/metabolismo , Propranolol/farmacologíaRESUMEN
Atypical antipsychotic (AA) drugs, such as risperidone, are associated with endocrine and metabolic side effects, including impaired bone mineral density (BMD) acquisition and increased fracture risk. We have previously shown that risperidone causes bone loss through the sympathetic nervous system and that bone loss is associated with elevated markers of thermogenesis in brown and white adipose tissue. Because rodents are normally housed in sub-thermoneutral conditions, we wanted to test whether increasing housing temperature would protect against bone loss from risperidone. Four weeks of risperidone treatment in female C57BL/6J mice at thermoneutral (28°C) housing attenuated risperidone-induced trabecular bone loss and led to a low-turnover bone phenotype, with indices of both bone formation and resorption suppressed in mice with risperidone treatment at thermoneutrality, whereas indices of bone resorption were elevated by risperidone at room temperature. Protection against trabecular bone loss was not absolute, however, and additional evidence of cortical bone loss emerged in risperidone-treated mice at thermoneutrality. Taken together, these findings suggest thermal challenge may be in part responsible for bone loss with risperidone treatment and that housing temperature should be considered when assessing bone outcomes of treatments that impact thermogenic pathways. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.