TY  - JOUR
AB  - 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.
AU  - Daamouch, S.*
AU  - Blüher, M.
AU  - Vázquez, D.C.*
AU  - Hackl, M.*
AU  - Hofbauer, L.C.*
AU  - Rauner, M.*
C1  - 70495
C2  - 55636
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - MiR-144-5p and miR-21-5p do not drive bone disease in a mouse model of type 1 diabetes mellitus.
JO  - JBMR Plus
VL  - 8
IS  - 5
PB  - Oxford Univ Press
PY  - 2024
SN  - 2473-4039
ER  - 

TY  - JOUR
AB  - Bone development and remodeling are controlled by the phosphoinositide-3-kinase (Pi3k) signaling pathway. We investigated the effects of downregulation of phosphatase and tensin homolog (Pten), a negative regulator of Pi3k signaling, in a mouse model of Pten deficiency in preosteoblasts. We aimed to identify mechanisms that are involved in the regulation of bone turnover and are linked to bone disorders. Femora, tibiae, and bone marrow stromal cells (BMSCs) isolated from mice with a conditional deletion of Pten (Pten cKO) in Osterix/Sp7-expressing osteoprogenitor cells were compared to Cre-negative controls. Bone phenotyping was performed by μCT measurements, bone histomorphometry, quantification of bone turnover markers CTX and procollagen type 1 N propeptide (P1NP), and three-point bending test. Proliferation of BMSCs was measured by counting nuclei and Ki-67-stained cells. In vitro, osteogenic differentiation capacity was determined by ALP staining, as well as by detecting gene expression of osteogenic markers. BMSCs from Pten cKO mice were functionally different from control BMSCs. Osteogenic markers were increased in BMSCs derived from Pten cKO mice, while Pten protein expression was lower and Akt phosphorylation was increased. We detected a higher trabecular bone volume and an altered cortical bone morphology in Pten cKO bones with a progressive decrease in bone and tissue mineral density. Pten cKO bones displayed fewer osteoclasts and more osteoblasts (P = .00095) per trabecular bone surface and a higher trabecular bone formation rate. Biomechanical analysis revealed a significantly higher bone strength (P = .00012 for males) and elasticity of Pten cKO femora. On the cellular level, both proliferation and osteogenic differentiation capacity of Pten cKO BMSCs were significantly increased compared to controls. Our findings suggest that Pten knockout in osteoprogenitor cells increases bone stability and elasticity by increasing trabecular bone mass and leads to increased proliferation and osteogenic differentiation of BMSCs.
AU  - Lorenz, J.*
AU  - Richter, S.*
AU  - Kirstein, A.S.*
AU  - Kolbig, F.*
AU  - Nebe, M.*
AU  - Schulze, M.*
AU  - Kiess, W.*
AU  - Spitzbarth, I.*
AU  - Klöting, N.
AU  - Le Duc, D.*
AU  - Baschant, U.*
AU  - Garten, A.*
C1  - 70309
C2  - 55505
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - Pten knockout in mouse preosteoblasts leads to changes in bone turnover and strength.
JO  - JBMR Plus
VL  - 8
IS  - 3
PB  - Oxford Univ Press
PY  - 2024
SN  - 2473-4039
ER  -