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

TL;DR

Losartan reduces TGFβ levels and improves bone health in a mouse model of Osteogenesis Imperfecta without harming the immune system.

Contribution

Losartan is shown to inhibit TGFβ signaling in osteoblasts, offering a safer alternative to direct TGFβ targeting for treating OI.

Findings

Losartan significantly reduces TGFβ levels and osteoclast activity in OIM mice.

Losartan increases cortical and trabecular bone thickness in OIM mice without affecting immune cells.

Losartan inhibits osteoblast differentiation by reducing SMAD2 phosphorylation.

Abstract

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.

•Losartan reverses excessive serum concentrations of TGFβ observed in OI.•Losartan reduces osteoclast/osteoblast numbers and activity as well as osteoblast differentiation without adversely effecting immunity.•Low dose losartan increases trabecular bone density and cortical thickness reducing tibial fractures in OIM mice.•Our data suggest that losartan may be a suitable candidate for repurposing as a new treatment for OI.

Losartan reverses excessive serum concentrations of TGFβ observed in OI.

Losartan reduces osteoclast/osteoblast numbers and activity as well as osteoblast differentiation without adversely effecting immunity.

Low dose losartan increases trabecular bone density and cortical thickness reducing tibial fractures in OIM mice.

Our data suggest that losartan may be a suitable candidate for repurposing as a new treatment for OI.

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