Sclerostin depletion may induce inflammation in the bone marrow

Abstract

Abstract The interactions between long-term hematopoietic stem cells (LT-HSCs) and cells in the bone microenvironment result in changes in stem cell behavior that are incompletely understood. Our goal is to define the molecular mechanisms that guide the behavior of LT-HSCs after exposure to an irregular bone marrow (BM) niche. Sclerostin (Sost) is a secreted Wnt antagonist that is important for bone homeostasis. We hypothesized that that loss of Sost would influence LT-HSC differentiation and migration. To test this, we performed hematopoietic progenitor transplantation assays to track donor-derived hematopoiesis in wild-type (WT) and Sost-knockout (KO) recipients. We observed increased frequencies of donor-derived myelopoiesis as well as decreased lymphopoiesis in WT to KO chimeras possibly due to an inflammatory microenvironment. We are currently investigating LT-HSC inflammatory response genes, such as C/EBP-beta and PU.1, as well as BM serum inflammatory cytokine levels. As the SostKO mice age, we observe extramedullary hematopoiesis (EMH) in the spleen compared to age matched controls. We hypothesize that changes in the BM microenvironment as well as cytokine levels in the spleen induce LT-HSC migration to the spleen. We are characterizing the EMH LT-HSC splenic niche by investigating LT-HSC localization as well as examining cytokines, such as CXCL12, known to induce LT-HSC migration to the spleen. Taken together, our data indicates that depletion of Sost in the bone regulates LT-HSC differentiation and migration. Our results could have significant impact on the tracking of hematopoietic function in human patients treated with SOST-depleting antibodies for bone diseases such as osteoporosis.