Grant: Operating Grant

Fibrillin-1 is one of the proteins present in bone. Osteoclasts are bone cells responsible for the normal replacement of bone, as well as for the abnormal destruction of bone in diseases such as osteoporosis, rheumatoid arthritis and bone metastasis. Abnormalities in the gene for fibrillin-1 cause several heritable disorders which lead to clinical problems in bone, including low bone mass, severe spinal deformities such as scoliosis and kyphosis, and exaggerated or reduced bone length. Marfan syndrome is the most frequent disorder in this group. We have recently discovered that fragments of fibrillin-1, similar to those released during normal bone replacement, act to restrict the formation of osteoclasts. We also found that a small fibrillin-1 fragment, when injected into normal mice, leads to a reduced number of osteoclasts in bone. Based on these findings, we propose that when osteoclasts degrade bone, they generate a self-limiting feedback through the production of small fibrillin-1 degradation products. In this application, we have the following four goals: 1) We intend to identify very small fibrillin-1 fragments that can reduce osteoclast formation in cell culture. 2) We will test whether these fragments have the ability to normalize exaggerated bone loss in various mouse models. 3) We aim to determine the underlying molecular mechanisms. 4) We will also analyze how mutations in fibrillin-1 alter these vital processes. For these goals, we will employ a unique combination of biochemical, cell biological and in vivo methods. This study could lead to results that could be readily translated into beneficial approaches to treat patients. For example, we anticipate finding novel small peptide inhibitors of osteoclast function which may be useful to both normalize bone structure in patients with fibrillin-1 abnormalities and more generally to prevent bone loss in patients with diseases associated with abnormal osteoclast activity, such as osteoporosis.