Mechanosensing in Bone

Abstract

The human skeleton is continually remodelled to adapt to force under the influence of gravity. Disuse of the skeleton leads to osteopenia whereas increased use leads to bone accrual. The process, by which skeletal cells sense and translate force into an anabolic response, is called mechanosensing. Downstream responses to physical force in the skeleton have been characterised, however the identities of the mechanosensing molecules are yet to be elucidated. Discovery of the mechanisms which underpin bone accrual is important for understanding the pathogenesis of bone wasting disorders such as osteoporosis.

The study of genetic disease, in which skeletal remodelling has been disrupted, can lead to the discovery of key molecules and pathways in this process. To this end, the focus of this thesis is the rare skeletal dysplasia frontometaphyseal dysplasia (FMD). Approximately 50% of FMD cases are caused by gain-of-function mutations in FLNA, which encodes the mechanosensitive protein filamin A, the other 50% of cases are unsolved.

In order to find other molecules which make up the skeletal mechanosensory network, gene discovery was undertaken in FLNA-mutation negative FMD individuals. The same mutation in MAP3K7, c.1454C>T, was found in 15 unrelated individuals. A further three patients were found to have unique mutations in the same gene (c.208G>C, c.299T>A, and c.502G>C). MAP3K7 encodes TGFβ-activated kinase 1 (TAK1) which phosphorylates and activates components of mitogen-activated protein kinase (MAPK) cascades. The discovered mutations were shown to increase the activation of the kinase and promote the anabolic response of the skeleton. Furthermore, I showed that mice which express constitutively mechanically-stimulated Flna have a hyperostotic phenotype. Taken together this indicates that filamin A is a potential mechanosensor in bone and transduces the force signal through activated TAK1 to bring about an anabolic response in the skeleton.