The role of the von-Hippel Lindau gene in osteocytes on B lymphocyte maturation and activation

Abstract

Abstract The von-Hippel Lindau protein (VHL) regulates hypoxia-inducible factor (HIF) degradation, which is involved in cellular adaptation to low oxygen environments. Conditional deletion of Vhl in osteoblasts and in hematopoietic progenitors have demonstrated a role for VHL in these cell types, but how changes in bone homeostasis affects immune development are not fully understood. Osteoblasts (OBs) support B cell development and mature into osteocytes (OCYs). To test if OCYs also support B cell development, we generated OCY-specific (Dmp1-Cre) conditional VHL knockout (cKO) mice. We previously found that cKO mice display dysregulated bone growth, high bone density, smaller bone marrow (BM) cavity volume, and overall decrease in BM cellularity compared to controls. In line with this, the frequencies and numbers of B cell precursors (B220+ IgM−), immature B (B220+ IgMint) and recirculating B (B220+ IgMhigh) cells in the bone marrow are significantly decreased. Although the absolute numbers of B cells in the spleens of cKOs were normal, frequency of B220+ CD19+ cells are decreased, while B1a (IgM+ CD5+) cells are increased. To define the mechanisms by which changes in the bone microenvironment affect B cells, we are investigating oxygenation status, vascular architecture and metabolic profiles of bone and B cells. We hypothesize that loss of VHL in OCYs could permanently and adversely affect B cell functional response. To test this, responses in T-independent and T-dependent antigens will be assessed in cKOs. Taken together, our data suggest that OCY-specific VHL deletion might be helpful to increase bone density, but at the expense of B cells.