title: Absence of sclerostin adversely affects B-cell survival.
abstract: Increased osteoblast activity in sclerostin-knockout (Sost(-/-)) mice results in generalized hyperostosis and bones with small bone marrow cavities resulting from hyperactive mineralizing osteoblast populations. Hematopoietic cell fate decisions are dependent on their local microenvironment, which contains osteoblast and stromal cell populations that support both hematopoietic stem cell quiescence and facilitate B-cell development. In this study, we investigated whether high bone mass environments affect B-cell development via the utilization of Sost(-/-) mice, a model of sclerosteosis. We found the bone marrow of Sost(-/-) mice to be specifically depleted of B cells because of elevated apoptosis at all B-cell developmental stages. In contrast, B-cell function in the spleen was normal. Sost expression analysis confirmed that Sost is primarily expressed in osteocytes and is not expressed in any hematopoietic lineage, which indicated that the B-cell defects in Sost(-/-) mice are non-cell autonomous, and this was confirmed by transplantation of wild-type (WT) bone marrow into lethally irradiated Sost(-/-) recipients. WT→Sost(-/-) chimeras displayed a reduction in B cells, whereas reciprocal Sost(-/-) →WT chimeras did not, supporting the idea that the Sost(-/-) bone environment cannot fully support normal B-cell development. Expression of the pre-B-cell growth stimulating factor, Cxcl12, was significantly lower in bone marrow stromal cells of Sost(-/-) mice, whereas the Wnt target genes Lef-1 and Ccnd1 remained unchanged in B cells. Taken together, these results demonstrate a novel role for Sost in the regulation of bone marrow environments that support B cells.
authors.affiliation: Quantitative and Systems Biology Graduate Program, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Cain
authors.forename: Randell
authors.initials: R
authors.lastname: Rueda
authors.forename: Bryce
authors.initials: B
authors.lastname: McLelland
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Collette
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Manilay
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D005260:Female; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D006410:Hematopoiesis; D007107:Immune System / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010011:Osteocytes / Q000166:cytology; D010641:Phenotype
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse