Semaphorin-3F, a potential biomarker for lymphatic anomalies and bone cell function


Semaphorin-3F, a potential biomarker for lymphatic anomalies and bone cell function


Solorzano E;Kelly M;Safadi F


Faseb Journal




Lymphatic anomalies (LA) are rare conditions characterized by abnormal vascularization of lymphatic vessels (lymphangiogenesis). Gorham‐Stout Disease (GSD) is an aggressive type of LA which invades cortical bone and makes it “disappear”. There is little evidence elucidating the etiology of GSD and its osteolytic tendencies due to the rarity of the disease. In addition, there are no biomarkers capable of predicting GSD progression or treatment outcome. Normal bone does not have lymphatic vessels. It is believed that in GSD lymphatic endothelial cells (LEC) undergo genetic changes early in development that facilitate their migration and vessel formation in bone. LECs and their secretome content (lymph) are likely both crucial to lymphatic migration into bone and the cortical destruction seen in GSD. In this study, we focused on the LEC secretome with the goal of identifying proteins capable of modifying LEC and bone cell interactions. We initially assessed the effects of normal LEC conditioned media (LEC‐CM) on bone cell differentiation and function in vitro, and found that LEC‐CM stimulates osteoclast differentiation. Next, we subjected LEC‐CM to mass spectrometry and over 500 proteins were identified; we focused specifically on Semaphorin‐3F (SEMA3F) as SEMA3F effectively inhibits lymphangiogenesis in part, by competing with vascular endothelial growth factor‐C (VEGF‐C), for binding to the neuropilin‐2 receptor. We measured mRNA expression of both SEMA3F and VEGF‐C in untreated and Rapamycin treated LECs, a clinically effective therapy for patients with lymphatic anomalies. SEMA3F mRNA expression was upregulated while VEGF‐C was downregulated in Rapamycin treated versus untreated LEC cultures. We next assessed the effects of exogenous SEMA3F on LEC viability and on osteoblast differentiation and function. We found that SEMA3F reduced LEC viability in a dose‐dependent fashion. In addition, SEMA3F inhibited osteoblast differentiation as measured by alkaline‐phosphatase activity and matrix mineralization independent of its effects on osteoblast viability or proliferation. Experiments are currently underway to determine the expression/localization of SEMA3F, VEGF‐C and neuropilin‐2 in lymphatic anomalies (LA) tissues obtained from pediatric patients at our facility. We expect that SEMA3F expression will be downregulated while VEGF‐C will be upregulated in LA compared to normal lymphatics. In summary, our data suggest that SEMA3F might be a possible biomarker for patient with LA conditions or contributes to their pathogenesis.


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Solorzano E;Kelly M;Safadi F, “Semaphorin-3F, a potential biomarker for lymphatic anomalies and bone cell function,” NEOMED Bibliography Database, accessed April 17, 2021,

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