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The systemic effects of sclerostin depletion in mouse hematopoiesis

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Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), 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 global 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 romosozumab-treated patients. Our overall goal was to define mechanisms that guide the behavior of long-term hematopoietic stem cells (LT-HSCs) after exposure to an irregular BM microenvironment. Sclerostin plays an important role in maintaining bone homeostasis, as demonstrated by the increased ratio of bone volume to total volume observed in Sost-/- mice. In this dissertation we assess 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. These 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 tumor necrosis factor  (TNF), interleukin-1 (IL-1) and monocyte chemoattractant protein 1 (MCP-1) in the serum of the Sost-/- BM. Additionally, alterations in erythrocyte differentiation in the BM and spleen of Sost-/- mice were observed. Taken together, this work indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM. These animal studies strongly recommend tracking of hematopoietic function in patients treated with romosozumab.

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