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. © 2012 American Society for Bone and Mineral Research.

New developments in osteoimmunology

“…It has been demonstrated that targeted disruption of sclerostin results in a decreased number of B cells due to elevated Bcell apop tosis. 40 As sclerostin is primarily expressed in osteocytes and is not expressed in any haematopoietic lineages, the Bcell defect in these mice was caused by the impaired pro duction of sclerostin by osteocytes. 40 These results suggest a novel role of osteocytes in the regulation of bone marrow environments that support immunological cells.…”

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

“…In addition, noncanonical Wnt signaling is also reported to sustain HSCs maintenance and aging [20,21]. Osteoblasts also support B-cell commitment and differentiation [22][23][24]. However, the function of Wnt signaling in osteoblastsupported B-cell development remains controversial.…”

“…Osteoblasts also support B-cell commitment and differentiation [22][23][24]. However, the function of Wnt signaling in osteoblastsupported B-cell development remains controversial.…”

“…These results highlight the complexity of the signaling cross-talk involved in bone marrow niches, which differ from the in vitro cultures of stromal cells. reported that the Sost-deficient mice have a significant increase of canonical Wnt signaling activity, bone mass, and defective B-cell survival [23]. Therefore, the effect of osteoblastic Wnts on B-cell lymphopoiesis also involves the action of cytokines or chemokines that were induced by Wnt signaling in osteoblasts.…”

Heavy Metal Ion Regulation of Gene Expression

“…Elimination of SOST gene expression prevented the depletion of Sca-1 ϩ -expressing bone marrow cells caused by Pb exposure. The drop in total Sca-1 ϩ MSCs in SOST-KO mice was not surprising given the bony overgrowth that occurs in animals devoid of sclerostin that narrows the marrow cavity (38). MSCs harvested from SOST-KO mice were less susceptible to Pb toxicity, showing improved osteoblastic activity.…”