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Published on: July 3, 2020
Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice
Cristine Donham1,2, Betsabel Chicana1,2, Alexander G Robling3,4
1Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA.
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.
Insights
Sclerostin antibody treatment in mice promoted granulocyte production and inflammation in bone marrow. Sclerostin deficiency impacts myeloid cell development and erythrocyte differentiation, suggesting roles in immune regulation.
Area of Science:
- Hematology
- Immunology
- Endocrinology
Background:
- Romosozumab, a sclerostin inhibitor, treats osteoporosis.
- Sclerostin deficiency in mice alters bone marrow immune cell development.
- Potential side effects of sclerostin inhibition on hematopoiesis are unknown.
Purpose of the Study:
- Investigate effects of short-term sclerostin depletion on hematopoiesis.
- Examine long-term Sost deficiency impact on hematopoietic stem cells.
- Determine sclerostin's role in bone marrow immune regulation.
Main Methods:
- Sclerostin antibody treatment in young mice (6 weeks).
- Bone marrow and spleen analysis of hematopoiesis.
- Hematopoietic stem cell transplantation into Sost-deficient mice.
- Measurement of inflammatory cytokines in serum.
Main Results:
- Sclerostin antibody and Sost deficiency induced myeloid-biased differentiation.
- Increased granulocytes observed in bone marrow and spleen.
- Elevated inflammatory cytokines (TNFα, IL-1α, MCP-1) in Sost-deficient serum.
- Alterations in erythrocyte differentiation noted.
Conclusions:
- Sclerostin deficiency promotes myeloid differentiation in bone marrow.
- Sclerostin plays a role in regulating myelopoiesis.
- Sclerostin influences inflammatory responses in the bone marrow microenvironment.
