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

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.

Affiliations

¹Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA

²Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA, USA

³Department of Pharmacology, University of New England, Biddeford, ME, USA

⁴Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA

⁵Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, USA

⁶Northern New England Clinical and Translational Research Network, MaineHealth, Portland, ME, USA

⁷Department of Biochemistry and University of Vermont Cancer Center, University of Vermont, Burlington, VT, USA

⁸Larner College of Medicine, University of Vermont Cancer Center, Burlington, VT, USA

⁹Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, USA

¹⁰Tufts University School of Medicine, Tufts University, Boston, MA, USA

Abstract and keywords

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.

Keywords: BONE; METABOLISM; OPIOIDS; MORPHINE; SEX DIFFERENCE; MIRNA

Links

DOI: 10.1002/jbmr.4690

PubMed: 36054037

WoS: 000859446700001

History

Received: 2022-03-17

Revised: 2022-07-30

Accepted: 2022-08-24

Cited Works (5)

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