Loss of the von-Hippel Lindau gene in osteocytes alters B lymphocyte development and immune response

Abstract

Abstract The von-Hippel Lindau protein (VHL) regulates hypoxia-inducible factor (HIF) degradation. 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. OBs mature into osteocytes (OCYs) and to test if OCYs also support B cell development, we generated OCY-specific (Dmp-Cre) conditional VHL knockout (cKO) mice. 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. These data suggest that the change in bone homeostasis adversely affects B cell development in a cell-extrinsic manner. Although the absolute numbers of B cells in the spleens of cKOs were normal, we hypothesized that loss of VHL in OCYs could permanently and adversely affect B cell functional response. To test this, VHL cKO mice were immunized with a T-independent antigen (NP-Ficoll). IgM and IgG3 antigen-specific titers to NP-Ficoll in VHL cKOs were similar to WT mice. Testing of B cell responses to T-dependent antigens (NP-OVA) is ongoing. Taken together, our data suggest that OCY-specific VHL deletion might be helpful to increase bone density, but at the expense of B cell numbers. Further investigation is required to understand the molecular mechanisms by which VHL in OCYs contribute to its putative role as a B cell niche cell.