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. 2008 Nov 4;105(44):16976-81.
doi: 10.1073/pnas.0802898105. Epub 2008 Oct 28.

Osteoblastic regulation of B lymphopoiesis is mediated by Gs{alpha}-dependent signaling pathways (V体育安卓版)

Joy Y Wu  1 , Louise E Purton, Stephen J Rodda, Min Chen, Lee S Weinstein, Andrew P McMahon, David T Scadden, Henry M Kronenberg
Affiliations

Osteoblastic regulation of B lymphopoiesis is mediated by Gs{alpha}-dependent signaling pathways

Joy Y Wu et al. Proc Natl Acad Sci U S A. .

Abstract

Osteoblasts play an increasingly recognized role in supporting hematopoietic development and recently have been implicated in the regulation of B lymphopoiesis. Here we demonstrate that the heterotrimeric G protein alpha subunit G(s)alpha is required in cells of the osteoblast lineage for normal postnatal B lymphocyte production. Deletion of G(s)alpha early in the osteoblast lineage results in a 59% decrease in the percentage of B cell precursors in the bone marrow VSports手机版. Analysis of peripheral blood from mutant mice revealed a 67% decrease in the number of circulating B lymphocytes by 10 days of age. Strikingly, other mature hematopoietic lineages are not decreased significantly. Mice lacking G(s)alpha in cells of the osteoblast lineage exhibit a reduction in pro-B and pre-B cells. Furthermore, interleukin (IL)-7 expression is attenuated in G(s)alpha-deficient osteoblasts, and exogenous IL-7 is able to restore B cell precursor populations in the bone marrow of mutant mice. Finally, the defect in B lymphopoiesis can be rescued by transplantation into a WT microenvironment. These findings confirm that osteoblasts are an important component of the B lymphocyte niche and demonstrate in vivo that G(s)alpha-dependent signaling pathways in cells of the osteoblast lineage extrinsically regulate bone marrow B lymphopoiesis, at least partially in an IL-7-dependent manner. .

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Trabecular bone is decreased in GsαOsxKO mice. (A) Hematoxylin and eosin–stained sections of proximal tibia at postnatal day 9 from WT and GsαOsxKO (KO) mice. (B) Osteoblast surface (ObS/BS) as a percentage of bone surface (n = 7 [WT] or 5 [KO]). (C) Quantitative real-time PCR for Gsα mRNA levels from GFP+ osteoblastic cells isolated by FACS. *P < .005.
Fig. 2.
Fig. 2.
B lymphopoiesis is impaired in GsαOsxKO mice. (A) Frequency of each lineage, shown as percentage of total marrow cells in postnatal day 10 bone marrow (n = 4). *, P < .005. (B) Gr-1+ myeloid cells and B220+ cells as a percentage of peripheral blood leukocytes at postnatal day 10 (n = 4). *, P < .005. (C) Number of splenic B220+ cells, as a percentage of the number of B220+ cells in WT littermates, is reduced in KO spleens at postnatal day 10 (n = 4). *, P < .001. (D) Percentage of bone marrow cells that are B220+/CD93+/IgM− (Left) or B220+/CD93+/IgM+ (Right) at postnatal day 8 (n = 10 WT or 7 KO). *, P < .05. (E) Percentage of B220+/CD19−/CD43+ prepro-B cells in bone marrow on postnatal day 8 (n = 6). (F) Percentages of pro-B (B220+/IgM−/CD43+) and pre-B (B220+/IgM−/CD43−) cells in bone marrow on postnatal day 8 (n = 3). *, P < .05.
Fig. 3.
Fig. 3.
Transplantation into WT microenvironment rescues B lymphopoiesis of GsαOsxKO bone marrow. (A) Adult WT lethally irradiated CD45.1+ mice received bone marrow transplants from WT or KO CD45.2+ donors. (B) Percentage of donor (CD45.1+) B220+ cells in recipients of WT and KO bone marrow transplantation. (C) Number of total bone marrow mononuclear cells (Left) and B220+/IgM− immature B cell precursors (Right) in recipients of WT (n = 5) and KO (n = 4) bone marrow.
Fig. 4.
Fig. 4.
IL-7 expression is reduced in GsαOsxKO osteoblasts. (A) CXCL12, IL-7, alkaline phosphatase (ALP), type I collagen (ColIa1), and osteocalcin (OC) mRNA levels in Osx-GFP:Cre+ osteoblasts from WT and KO littermates. *, P < .02. (B) Pro-B and pre-B cells as percentages of bone marrow cells in WT (n = 7) and KO (n = 3) mice injected with IL-7 or vehicle.
Fig. 5.
Fig. 5.
Transgenic mice expressing the constitutively active PPR in osteoblasts have defective production of B220+IgM− lymphocytes. Shown are the frequencies of bone marrow leukocytes that are B220+, B220+/IgM−, or B220+/IgM+ in 2 week-old WT (n = 2) or transgenic (Tg, n = 4) mice. *, P < .005.
Fig. 6.
Fig. 6.
Model of osteoblastic regulation of B lymphopoiesis. Within the bone marrow of early postnatal mice, B cell precursors are located in close proximity to cells of the osteoblast lineage. Stimulation of Gsα-coupled GPCRs on the osteoblast surface leads to up-regulation of PKA target genes. These may include genes encoding for factors that stimulate B lymphopoiesis, such as IL-7.
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