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, Francesco Ramirez

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numberddq409
Pages (from-to)4790-4798
Number of pages9
JournalHuman molecular genetics
Volume19
Issue number24
DOIs
StatePublished - Dec 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Nistala, H., Lee-Arteaga, S., Carta, L., Cook, J. R., Smaldone, S., Siciliano, G., Rifkin, A. N., Dietz, H. C., Rifkin, D. B., & Ramirez, F. (2010). Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome. Human molecular genetics, 19(24), 4790-4798. [ddq409]. https://doi.org/10.1093/hmg/ddq409