Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice.

International journal of molecular sciences 2021 Aug 24

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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 (Sost-/-) 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 Sost deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of Sost-/- mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT→Sost-/- 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 TNFα, IL-1α, and MCP-1 in Sost-/- BM serum. 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.

Citation

Cristine Donham, Betsabel Chicana, Alexander G Robling, Asmaa Mohamed, Sonny Elizaldi, Michael Chi, Brian Freeman, Alberto Millan, Deepa K Murugesh, Nicholas R Hum, Aimy Sebastian, Gabriela G Loots, Jennifer O Manilay. Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice. International journal of molecular sciences. 2021 Aug 24;22(17)