The extracellular matrix (ECM) is a highly dynamic component of the developing -transcriptional control of the secreted skeleton. While the transcriptional control of ECM composition during skeletal development is intensively studied, the post-- components of the ECM and its regulators are relatively poorly understood. We have identified a novel class of regulator of secreted proteins, the first known secreted protein tyrosine kinase (VLK) that is essential for normal endochondral bone formation. We find that VLK phosphorylates a wide range of secreted proteins with established roles in skeletal development and maintenance of bone mass. VLK also phosphorylates resident ER proteins with specific roles in bone ECM secretion, and thus may modify secreted proteins not only directly, but also indirectly through control of the secretion process in -mediated phosphorylations both during endochondral ossification and during fracture endochondral cells. In this proposal, we plan to establish the functional role of VLK- repair. We will use a combination of in vitro and in vivo approaches to identify substrates for VLK in endochondral cells, identify spatial and temporal patterns of VLK mediated phosphorylations in vivo, establish how VLK modifies chondrocyte differentiation and endochondral ossification, and examine the function of VLK phosphorylation of specific secreted substrates. These studies will define a new mechanism for the regulation of ECM function in bone, providing a new approach to the therapeutic modulation of skeletal development, homeostasis, and repair.
Diseases associated with pathological changes of the extracellular matrix have a tremendous impact on the health and well-being of all US citizens. In the skeleton, these changes can include reduced bone density with age, osteoarthritis, and increased bone remodeling during tumor metastasis. We have identified a new mechanism for the regulation of proteins that control bone and cartilage matrix homeostasis, with substantial implications for new therapeutic approaches to skeletal disease.
