Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice

Abstract

Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), has been approved for treatment of postmenopausal women with osteoporosis at a high risk for fracture. Previous work in sclerostin global knockout (<i>Sost</i>^-/-) mice indicated alterations in immune cell development in the bone marrow (BM), which could be a possible side effect in romosozumab-treated patients. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young mice receiving sclerostin antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term <i>Sost</i> deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of <i>Sost</i>^-/- mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT→<i>Sost</i>^-/- chimeras, indicating myeloid-biased differentiation in <i>Sost</i>-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α, and MCP-1 in <i>Sost</i>^-/- BM serum. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of <i>Sost</i>^-/- mice. Taken together, our current study indicates novel roles for <i>Sost</i> in the regulation of myelopoiesis and control of inflammation in the BM.