Journal Article

Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome

Harikiran Nistala, Sui Lee-Arteaga, Luca Carta, Jason R. Cook, Silvia Smaldone, Gabriella Siciliano, Aaron N. Rifkin, Harry C. Dietz, Daniel B. Rifkin and Francesco Ramirez

in Human Molecular Genetics

Volume 19, issue 24, pages 4790-4798
Published in print December 2010 | ISSN: 0964-6906
Published online September 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq409
Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome

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Reduced bone mineral density (osteopenia) is a poorly characterized manifestation of pediatric and adult patients afflicted with Marfan syndrome (MFS), a multisystem disorder caused by structural or quantitative defects in fibrillin-1 that perturb tissue integrity and TGFβ bioavailability. Here we report that mice with progressively severe MFS (Fbn1mgR/mgR mice) develop osteopenia associated with normal osteoblast differentiation and bone formation. In vivo and ex vivo experiments, respectively, revealed that adult Fbn1mgR/mgR mice respond more strongly to locally induced osteolysis and that Fbn1mgR/mgR osteoblasts stimulate pre-osteoclast differentiation more than wild-type cells. Greater osteoclastogenic potential of mutant osteoblasts was largely attributed to Rankl up-regulation secondary to improper TGFβ activation and signaling. Losartan treatment, which lowers TGFβ signaling and restores aortic wall integrity in mice with mild MFS, did not mitigate bone loss in Fbn1mgR/mgR mice even though it ameliorated vascular disease. Conversely, alendronate treatment, which restricts osteoclast activity, improved bone quality but not aneurysm progression in Fbn1mgR/mgR mice. Taken together, our findings shed new light on the pathogenesis of osteopenia in MFS, in addition to arguing for a multifaceted treatment strategy in this congenital disorder of the connective tissue.

Journal Article.  5204 words.  Illustrated.

Subjects: Genetics and Genomics

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