Connor Carpenter

Introduction. Gorham-Stout Disease (GSD) is also known as “vanishing bone disease” due to the capacity to cause sudden and rapid bone loss in children and young people. In healthy individuals, lymph vessels are not observed in bone marrow or cortical bone.³ The disease is characterized by lymphatic invasion of bone that progresses to unchecked resorption without new bone deposition. The full details of the cellular mechanisms associated with GSD have not yet been elucidated. The rarity of GSD makes it difficult to study, however recent reviews of all reported cases highlight the role of immune and lymph system pathophysiology.^1,7  Methods. A comprehensive review of the literature was conducted to synthesize mechanistic results from animal model studies and clinical findings from case reports. VEGFC/VEFR3 signaling, lymphatic endothelial cell (LECs) mediated activation of osteoclasts, and immunomodulatory therapy are the current primary topics of focus within GSD research.^2,4,5 Inducible pathologic lymphangiogenesis occurs in Osx-tTA;TetO-Vegfc transgenic mice that selectively overexpress VEGFC. This mouse model was used in many of the articles reviewed to analyze bone and lymphatic interaction in the context of a GSD phenotype.  Results. VEGFC overexpression in bone in mice leads to lymphatic invasion of bone and osteolysis.² In humans, local VEGFC elevation is more commonly observed than systemic elevation while serum IL-6 levels are elevated systemically.^2,8 During an inflammatory response, like what is seen in GSD, cytokines activate osteoclasts and inhibit osteoblasts.⁸ One study found that serum taken from a GSD patient stimulated osteoclastogenesis while another found that an osteoclast inhibitor prevented bone lose in mice with a GSD phenotype.^2,6 Additionally, LECs do not directly degrade bone, which indicates the significant role of osteoclasts. To further understand how lymphatic invasion of the bone occurs, one study conducted lineage tracing on LECs within bone and found that they originated from nearby periosseous muscle.⁴ The same study also found that no lymphatic invasion occurred in osteoclast knockout mice despite VEGFC overexpression.⁴ The interactions between LECs and osteoclasts has been observed as LECs release macrophage colony stimulating factor and osteoclasts can produce VEGFC.^8,9 Limited clinical trials showing successful treatment of GSD with Sirolimus, an mTOR inhibitor, imply higher-level immune regulation is involved in the pathophysiology.⁵ Conclusion. GSD is precipitated by local lymphangiogenesis due to VEGFC overexpression. Osteoclast stimulation leads to bony invasion and subsequent osteolysis. The connection between these two points needs further research to be understood. LEC and osteoclast signaling should be evaluated in addition to the mTOR regulatory pathway.

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