Osteoblastic regulation of B lymphopoiesis is mediated by G
            <sub>s</sub>
            α-dependent signaling pathways

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

doi:10.1073/pnas.0802898105

Cited by 230 publications

(222 citation statements)

References 42 publications

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“…Osteoblasts increase after ovariectomy in response to increased bone resorption, a phenomenon known as coupling (20). Moreover, osteoblasts provide factors such as IL-7 and CXCL-12 that support B cell development (21)(22)(23)(24). Consistent with the idea that the failure to increase B cells was due to reduced support by osteoblast-lineage cells, IL-7 mRNA in bone was increased by ovariectomy in Tnfsf11 f/f but not Tnfsf11 ⌬Ot mice (Fig.…”

Section: Osteocyte Rankl Is Required For Ovariectomy-induced Bonesupporting

confidence: 71%

“…Many of these previous studies include evidence that osteoblast-lineage cells support B cell development by expressing IL-7 and CXCL-12 (22,23,32). We found that IL-7 and CXCL-12 mRNAs were elevated by ovariectomy in control mice but not in Tnfsf11 ⌬Ot mice.…”

Section: Discussionsupporting

confidence: 52%

“…For example, ablation of osteoblasts reduces B cell number before reductions in other hematopoietic lineages (32). In addition, suppression of PTH receptor signaling specifically in osteoblasts reduces B cell number (22). Perhaps most relevant to the current work, suppression of bone remodeling by administration of bisphosphonates is sufficient to reduce the number of osteoblasts on the bone surface and the number of B cells in the bone marrow of mice (23,33).…”

Section: Discussionmentioning

confidence: 73%

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RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice

Fujiwara

Piemontese

Liu

et al. 2016

Journal of Biological Chemistry

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Edited by Luke O'NeillThe cytokine receptor activator of NFB ligand (RANKL) produced by osteocytes is essential for osteoclast formation in cancellous bone under physiological conditions, and RANKL production by B lymphocytes is required for the bone loss caused by estrogen deficiency. Here, we examined whether RANKL produced by osteocytes is also required for the bone loss caused by estrogen deficiency. Mice lacking RANKL in osteocytes were protected from the increase in osteoclast number and the bone loss caused by ovariectomy. Moreover, these mice did not exhibit the increase in bone marrow B lymphocytes caused by ovariectomy that occurred in control littermates. Deletion of estrogen receptor ␣ from B cells did not alter B cell number or bone mass and did not alter the response to ovariectomy. In addition, lineage-tracing studies demonstrated that B cells do not act as osteoclast progenitors in estrogen-replete or estrogen-deficient mice. Taken together, these results demonstrate that RANKL expressed by osteocytes is required for the bone loss as well as the increase in B cell number caused by estrogen deficiency. Moreover, they suggest that estrogen control of B cell number is indirect via osteocytes and that the increase in bone marrow B cells may be a necessary component of the cascade of events that lead to cancellous bone loss during estrogen deficiency. However, the role of B cells is not to act as osteoclast progenitors but may be to act as osteoclast support cells.

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Section: Osteocyte Rankl Is Required For Ovariectomy-induced Bonesupporting

confidence: 71%

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 73%

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RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice

Fujiwara

Piemontese

Liu

et al. 2016

Journal of Biological Chemistry

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“…Furthermore, reduced marrow IL-6 mRNA expression in Prg4 mutant mice may contribute to decreased frequency of B-lymphocytic cells, because IL-6 supports physiological B-lymphopoiesis. 28,53,54 Similar to Prg4 mutant mice, mice with an osteoprogenitor cell G s ␣ deficiency (a downstream mediator of the PPR) have decreased peripheral blood and marrow B-lymphocytic cells, 55 suggesting that osteoblast cell signaling also could play a role in Prg4 mutant mice. The unexpected finding that PTH induced normalization of peripheral blood neutrophils and marrow B-lymphocytic cells in Prg4 mutant mice to wild-type levels may be associated with the PTH-induced increase in marrow SDF-1 protein in Prg4 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Novince¹,

Koh²,

Michalski³

et al. 2011

The American Journal of Pathology

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Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa varapericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4 ؊/؊ mutant and Prg4 ؉/؉ wild-type mice were treated daily with intermittent PTH (residues 1-34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220 ؉ (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin ؊ Sca-1 ؉ c-Kit ؉ (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTHstimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.

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“…Several lines of evidence suggest that these skeletal and hematopoietic systems in the bone microenvironment are not only structurally adjacent, but also functionally interactive (1)(2)(3)(4). Maintenance of the hematopoietic stem cell niche and B-lymphocyte differentiation has been attributed to osteoblasts (1,2,5). T lymphocytes support anabolic actions of parathyroid hormone (PTH) in bone via production of osteoblast stimulating Wnt-10b (6).…”

mentioning

confidence: 99%

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone

Cho

Soki

Koh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

198

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Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms + myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTHinduced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68 + cells, whereas clodronate liposome-treated mice had increased CD68 + and CD163 + cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis.

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Osteoblastic regulation of B lymphopoiesis is mediated by G _s α-dependent signaling pathways

Cited by 230 publications

References 42 publications

RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice

RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone

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Osteoblastic regulation of B lymphopoiesis is mediated by G s α-dependent signaling pathways

Cited by 230 publications

References 42 publications

RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice

RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone

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Osteoblastic regulation of B lymphopoiesis is mediated by G _s α-dependent signaling pathways