Losartan alters osteoblast differentiation and increases bone mass through inhibition of TGF B signalling in vitro and in an OIM mouse model.

Autor:	Morita M; Mellanby Centre for Musculoskeletal Research and Division of Clinical Medicine, University of Sheffield, Beech Hill Road, Sheffield, UK., Arshad F; Mellanby Centre for Musculoskeletal Research and Division of Clinical Medicine, University of Sheffield, Beech Hill Road, Sheffield, UK., Quayle LA; Department of Computing, Sheffield Hallam University, Cantor Building, Arundel Street, Sheffield, UK., George CN; Mellanby Centre for Musculoskeletal Research and Division of Clinical Medicine, University of Sheffield, Beech Hill Road, Sheffield, UK., Lefley DV; Mellanby Centre for Musculoskeletal Research and Division of Clinical Medicine, University of Sheffield, Beech Hill Road, Sheffield, UK., Kalajzic I; Reconstructive Sciences, UConn Health, Farmington, CT. USA., Balsubramanian M; Mellanby Centre for Musculoskeletal Research and Division of Clinical Medicine, University of Sheffield, Beech Hill Road, Sheffield, UK.; Highly specialised Osteogenesis Imparfecta Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK., Cebe T; INSIGNIO Institute for in silico Medicine and the Kroto Research Institute, Department of Materials Science and Engineering, University of Sheffield, Sheffield, UK., Reilly G; INSIGNIO Institute for in silico Medicine and the Kroto Research Institute, Department of Materials Science and Engineering, University of Sheffield, Sheffield, UK., Bishop NJ; Mellanby Centre for Musculoskeletal Research and Division of Clinical Medicine, University of Sheffield, Beech Hill Road, Sheffield, UK.; Highly specialised Osteogenesis Imparfecta Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK., Ottewell PD; Mellanby Centre for Musculoskeletal Research and Division of Clinical Medicine, University of Sheffield, Beech Hill Road, Sheffield, UK.
Jazyk:	angličtina
Zdroj:	Bone reports [Bone Rep] 2024 Jul 25; Vol. 22, pp. 101795. Date of Electronic Publication: 2024 Jul 25 (Print Publication: 2024).
DOI:	10.1016/j.bonr.2024.101795
Abstrakt:	Excessive production of Transforming Growth Factor β (TGFβ) is commonly associated with dominant and recessive forms of OI. Previous reports have indicated that administration of TGFβ-targeted antibodies maybe of potential therapeutic benefit to OI patients. However, direct targeting of TGFβ is likely to cause multiple adverse effects including simulation of autoimmunity. In the current study we use patient-derived normal and OI fibroblasts, osteoblasts and OIM mouse models to determine the effects of Losartan, an angiotensin II receptor type 1 (AT1) antagonist, on TGFβ signalling and bone morphology in OI. In OIM mice bred on a mixed background administration of 0.6 g/L losartan for 4 weeks was associated with a significant reduction in TGFβ from 79.2 g/L in the control to 60.0 ng/ml following losartan ( p  < 0.05), reduced osteoclast activity as measured by CTX from 275.9 ng/ml in the control to 157.2 ng/ml following 0.6 g/L of losartan (p < 0.05) and increased cortical bone thickness ( P  < 0.001). Furthermore in OIM mice bred on a C57BL/6 background 0.6 g/L losartan increased trabecular bone volume in the tibiae ( P  < 0.05) and the vertebrae ( P  < 0.01), increased cortical bone thickness ( P  < 0.001) reduced the trabecular pattern factor ( P  < 0.01 and P < 0.001 for the tibiae and vertebrae respectively), reduced osteoclast ( P  < 0.05) and osteoblast (P < 0.01) numbers as well as reducing the area of bone covered by these cell types. Interestingly, losartan did not affect immune cells infiltrating into bone, nor did this drug alter TGFβ signalling in normal or OI fibroblasts. Instead, losartan reduced SMAD2 phosphorylation in osteoblasts, inhibiting their ability to differentiate. Our data suggest that losartan may be an effective treatment for the bone-associated dysmorphia displayed in OI whilst minimising potential adverse immune cell-related effects. Competing Interests: NJB is global chief investigator of the Ultragenyx-funded studies (ORBIT, COSMIC) of setrusumab in children and young adults with OI and has consulted with Alexion, Mereo and Rampart and has been DMEC chair for a Pfizer study (recifercept in achondroplasia). No other authors have relevant conflicts of interest to declare. (© 2024 The Authors.)
Databáze:	MEDLINE
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