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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 ( Fbn1 mgR/mgR   mice) develop osteopenia associated with normal osteoblast differentiation and bone formation.  In vivo  and  ex vivo  experiments, respectively, revealed that adult  Fbn1 mgR/mgR   mice respond more strongly to locally induced osteolysis and that  Fbn1 mgR/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  Fbn1 mgR/mgR   mice even though it ameliorated vascular disease. Conversely, alendronate treatment, which restricts osteoclast activity, improved bone quality but not aneurysm progression in  Fbn1 mgR/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.

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