Sclerostin depletion induces inflammation in the bone marrow of mice

Abstract

Romosozumab, a humanized monoclonal antibody specific for sclerostin, has been approved for treatment of post-menopausal women with osteoporosis at high risk for fracture. In several Phase III clinical trials, romosozumab decreased the risk of vertebral fractures up to 73% and increased total hip area bone mineral density by 3.2%. Previous work in 12 to 15-week-old sclerostin-knockout (Sost-/-) mice indicated that changes in immune cell development occur in the bone marrow (BM), which could be a possible side effect to follow in human patients. Our overall goal was to define the mechanisms that guide behavior of long-term hematopoietic stem cells (LT-HSCs) after exposure to an irregular BM microenvironment. SOST plays an important role in maintaining bone homeostasis, as demonstrated by the increased ratio of bone volume to total volume observed in Sost-/- mice. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young (8 week-old) mice receiving sclerostin-antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost-deficiency on wild-type (WT) LT-HSCs transplanted into older (16-22 week-old) cohorts of Sost-/- mice. Our analyses revealed an increased frequency of granulocytes and decreased frequency of lymphocytes in the BM of Scl-Ab treated mice and WT→Sost-/- hematopoietic chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNF-alpha, IL-1-alpha and MCP-1 in the serum of the Sost-/- BM. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost-/- mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM. Our animal studies strongly recommend tracking of hematopoietic function in patients treated with romosozumab.