MiR-144-5p and miR-21-5p do not drive bone disease in a mouse model of type 1 diabetes mellitus

Souad Daamouch; Matthias Blüher; David Carro Vázquez; Matthias Hackl; Lorenz C Hofbauer; Martina Rauner

doi:10.1093/jbmrpl/ziae036

MiR-144-5p and miR-21-5p do not drive bone disease in a mouse model of type 1 diabetes mellitus

JBMR Plus. 2024 Apr 6;8(5):ziae036. doi: 10.1093/jbmrpl/ziae036. eCollection 2024 May.

Authors

Souad Daamouch¹, Matthias Blüher², David Carro Vázquez³, Matthias Hackl³, Lorenz C Hofbauer¹, Martina Rauner¹

Affiliations

¹ Department of Medicine III, Center for Healthy Aging, Technische Universität Dresden, Dresden, Saxony, 01307, Germany.
² Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Saxony, 04109, Germany.
³ TAmiRNA, Vienna, 1110, Austria.

Abstract

The increased risk of fractures in patients with type 1 diabetes mellitus (T1DM) is nowadays well recognized. However, the exact mechanism of action of diabetic bone disease has not been fully elucidated. MicroRNAs (miRNAs) are gene regulators that operate post-transcriptionally and have been implicated in the development of various metabolic disorders including T1DM. Previous studies have implicated a role for miR-144-5p and miR-21-5p, which are involved in controlling oxidative stress by targeting Nrf2, in T1DM. To date, it is unclear whether miR-144-5p and miR-21-5p affect bone health in T1DM. Thus, this study aimed to investigate the influence of miR-144-5p and miR-21-5p knockdown in the development of bone disease in T1DM male mice. Therefore, T1DM was induced in 10-wk-old male mice using streptozotocin (STZ). One week later, after development of hyperglycemia, antagomir-144-5p and antagomir-21-5p or their non-targeting control were administered at 10 mg/kg BW once a week until the end of the experiment. At 14 wk of age, glucose levels, bone, and fat mass were analyzed. The results revealed that treating T1DM male mice with antagomir-144-5p and antagomir-21-5p did not protect against diabetes development or bone loss, despite the successful downregulation of the miRNAs and the normalization of Nrf2 mRNA levels in bone tissue. Histological and serological parameters of bone formation or resorption were not altered by the antagomir treatment. Finally, we measured the expression of miRNA-144-5p or miRNA-21-5p in the serum of 30 individuals with T1DM and compared them to non-diabetic controls, but did not find an altered expression of either miRNA. In conclusion, the knockdown of miR-144-5p and miR-21-5p does not affect STZ-induced diabetes development or loss of bone mass in male mice. However, it does normalize expression of the anti-oxidant factor Nrf2 in diabetic bone tissue.

Keywords: T1DM; antagomir; bone loss; miR-144-5p; miR-21-5p.