Molecular crosstalk and matrix metalloproteinases in Generalized Lymphatic Anomaly (GLA) and Gorham-Stout Syndrome (GSS) patients
Investigator: Ramani Ramchandran, PhD
Institute: Medical College of Wisconsin
Gorham-Stout Syndrome (GSS), also called “vanishing bone disease,3” is a lymphatic vessel associated syndrome whose etiology is unknown. GSS is a rare skeletal condition characterized by the uncontrolled proliferation of lymphatic endothelial cells (LECs) leading to distended, thin-walled vascular or lymphatic channels within the bone3. This leads to resorption and replacement of bone with angiomas and/or fibrosis. Generalized lymphatic anomaly (GLA) is distinct from GSS in that this condition is marked by the presence of cysts that result from an increase both in the size and number of thin-walled lymphatic channels that are abnormally interconnected and dilated, and for the most part lacks the bone component. Patients with GSS or GLA have very limited treatment options, and any scientific research that leads to the underlying mechanism associated with GLA or GSS is likely to propel the discovery of therapeutics for these conditions. Dr. Ramchandran’s long-term goal is to identify the underlying cause for the pathogenesis of GSS and GLA. The objective of this project is to isolate and study the cell types lymphatic endothelial cells (LECs), bone-forming (osteoblast – OBs), and bone-reabsorbing (osteoclasts – OCs) cells that are likely to be responsible for the pathogenesis of these conditions. Preliminary studies funded by LMI have led to the successful isolation and culture of LECs from the lymph fluid. The lab has also successfully differentiated multi-nucleated osteoclasts with bone-clearing activity, and positivity for markers (TRAP and actin rings) from monocytes isolated from GLA blood. Based on these pilot studies, they hypothesize that cross communication between LECs and OBs/OCs in GSS patients may be altered resulting in alterations in bone recycling mechanisms and or LEC growth thus contributing to the pathogenesis of GSS. In this proposal, they will attempt into quantify osteoclast function in the presence of lymph fluid from LMs, GSS, and GLA patients, and to identify signaling pathways activated in osteoclasts in response to GSS/GLA lymph. Accomplishing the two aims will greatly increase our understanding of the role of LECs and bone forming cells in the pathogenesis of GSS and GLA.
Immunohistochemical characterization of the extraskeletal changes in generalized lymphatic anomaly (GLA) and Gorham Stout disease (GSD)
Investigator: Erik A. Eklund, MD, PhD
Institute: Clinical Sciences, Experimental Paediatrics, Lund University, Lund, Sweden
GSD is a rare disorder characterized by replacement of bone by an endothelial-rich fibrous tissue, and occasionally, extraskeletal invasion with lymphatic vessels in spleen, liver and lungs/pleurae. GLA is a related disorder with a more widespread extraskeletal pattern. The cellular and molecular processes leading up to extraskeletal symptoms (e.g. chylothorax) in GLA/GSD are poorly understood, but probably involve osteoclast activation and production of lymphangiogenetic cytokines/growth factors. In this project, Dr. Eklund’s lab employs an immunohistochemical approach to map changes in extraskeletal tissue from these patients. Sections from pleurae, lungs, spleen and bone marrow are analyzed for the presence or absence of osteoclasts, immune-derived cells, cytokines, cytokine receptors, lymphatic and blood vessels, and proliferating endothelium. Further, activation of several intracellular signaling pathways, such as MAP kinases, are investigated. Secondary changes in matrix composition, with the focus on proteoglycans, are also analyzed. They aim at identifying important molecular and cellular players in order to find targets for future therapeutic intervention. The project is run in collaboration with Dr. Lopez Gutierrez, Madrid, but the lab aims at including patient material from other sites as well.