Sustained Morphine Delivery Suppresses Bone Formation and Alters Metabolic and Circulating miRNA Profiles in Male C57BL/6J Mice.
Sustained Morphine Delivery Suppresses Bone Formation and Alters Metabolic and Circulating miRNA Profiles in Male C57BL/6J Mice.
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DOI：
10.1002/jbmr.4690
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发表时间：
2022-11
影响因子：
6.2
通讯作者：
Motyl, Katherine J.
中科院分区：
文献类型：
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作者：
Carvalho, Adriana Lelis;Brooks, Daniel J.;Barlow, Deborah;Langlais, Audrie L.;Morrill, Breanna;Houseknecht, Karen L.;Bouxsein, Mary L.;Lian, Jane B.;King, Tamara;Farina, Nicholas H.;Motyl, Katherine J.
阿片类药物的使用对骨骼健康有害，对骨转换造成间接和直接影响。虽然这些作用的机制尚不完全清楚，但最近的研究将长期使用阿片类药物与循环miRNA的改变联系起来。在这里，我们开发了阿片类药物诱导的骨丢失模型，以了解骨转换并识别候选的miRNA介导的调节机制。我们通过使用皮下渗透微型泵用载体（0.9%盐水）或吗啡（17 mg/kg）处理25天来评估持续吗啡处理对雄性和雌性C57 BL/6 J小鼠的影响。吗啡处理的小鼠具有更高的能量消耗和呼吸商，表明向碳水化合物代谢的转变。显微计算机断层扫描（μCT）分析表明，骨结果存在性别差异，其中吗啡治疗的雄性小鼠骨小梁体积分数（Tb.BV/TV）降低（15%），Tb.BV/TV降低（15%）。与载体相比，股骨远端的骨矿物质密度（BMD）（14%）。相反，吗啡治疗后女性的骨微结构没有改变。组织形态计量学分析表明，在雄性动物中，与溶剂相比，吗啡降低了骨形成率，但破骨细胞参数无差异。此外，吗啡降低了男性胫骨中骨形成标记基因（Bglap和Dmp 1）的表达。循环miRNA谱的变化在男性中是明显的，与女性中的两个差异表达的miRNA相比，有14个差异表达的miRNA与吗啡治疗相关。在雄性中，靶点分析表明miR-223- 3 p靶向缺氧诱导因子（HIF）信号通路，miR-484、-223-3p和-328-3p靶向脂肪酸代谢。因此，在吗啡处理的骨中，miR-223- 3 p靶点（包括Igf 1 r和Stat 3）的表达较低。总之，我们已经建立了一个模型，其中吗啡导致男性骨小梁形成较低，并确定了潜在的介导miRNA。了解阿片类药物引起骨丢失的性别特异性机制对于改善阿片类药物对骨骼的不良影响的管理至关重要。
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. 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. Microcomputed 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 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, compared to 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.
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影响因子：
--
作者：
Farina NH;Ramsey JE;Cuke ME;Ahern TP;Shirley DJ;Stein JL;Stein GS;Lian JB;Wood ME
通讯作者：
Wood ME
影响因子：
8
作者：
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影响因子：
6.2
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通讯作者：
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影响因子：
13.5
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通讯作者：
Zhang, Bixiang
影响因子：
3.3
作者：
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通讯作者：
Meier, Christian