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 (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.
Highlights
Two rare human bone disorders, sclerosteosis and van Buchem disease, are characterized by dramatic increases in bone mineral density (BMD) and have been genetically traced to mutations in the Sost gene locus, which codes for sclerostin [1,2]
Given the known relationship between Wnt signaling on hematopoietic stem cell self-renewal and function [37], and that sclerostin is a Wnt signaling antagonist [3,38], we hypothesized that removal of sclerostin through administration of neutralizing antibodies would promote hematopoietic stem cells (HSCs) self-renewal
sclerostin antibody (Scl-Ab) treatment resulted in increased trabecular volume/total volume (BV/TV) and midshaft cortical thickness, similar to that observed in the Sost−/− mice (Figure 1B–D) [34,39]
Summary
Two rare human bone disorders, sclerosteosis and van Buchem disease, are characterized by dramatic increases in bone mineral density (BMD) and have been genetically traced to mutations in the Sost gene locus, which codes for sclerostin [1,2]. When Wnt is inhibited, osteoprotegerin (OPG) is decreased, and there is an increase in bone resorption [5]. In Sost−/− mice where Wnt is upregulated, OPG is concurrently increased [5]. This demonstrates that Sost regulates bone formation, it regulates bone resorption. The increase in BMD in Sost−/− mice and in humans with decreased
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