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Background Von Hippel-Lindau protein deficiency leads to cellular and tissue false sense of hypoxia (pseudohypoxia), driving erythropoiesis, angiogenesis, and dysglycemia. The impact of partial VHL protein deficiency, caused by heterozygous VHL gene alterations on diabetes and cardiovascular risk has not been investigated. Hence, in the current study we assessed a possible association between VHL genotype and cardiovascular risk based on a the UK Biobank genomic and clinical data. Methods Demographic, clinical and biochemical data were extracted, and exome analysis, focusing on the VHL gene locus was performed for all patients (n = 460,430). Variant severity was sub-categorized into low (5’— and 3’—untranslated region (UTR)), medium (missense, in-frame indels), and high-risk (nonsense, splice-site, and frameshift). Metabolic and cardiovascular outcomes were compared between VHL variant carriers vs. non-carriers. Results VHL gene variant carriers (n = 2516) had an increased risk of diabetes (p = 0.04) and cerebrovascular accidents (CVA, p = 0.03) vs. controls, more pronounced in higher severity variants. 5’UTR variants were associated with an increased risk of diabetes (p < 0.001) and a younger age at diabetes diagnosis (p = 0.003) compared to other variants. In multivariable analysis, 5’UTR variants were associated with an increased risk of diabetes (odds ratio 2.97, 95% confidence interval 1.78–4.80, p < 0.001). Increasing reticulocyte levels positively correlated with metabolic syndrome markers (serum glucose, glycated hemoglobin, and triglyceride levels) and mediated the increased diabetes risk of 5’UTR variant carriers. Conclusions VHL gene variant carriers have an increased risk of diabetes and CVA. Mediation analysis suggests pseudohypoxia as a possible mechanism. Graphical abstract

Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD: (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis.