Parathyroid hormone effectively induces mobilization of progenitor cells without depletion of bone marrow

Brunner, Stefan; Zaruba, Marc-Michael; Hüber, Bruno; Dávid, Róbert; Vallaster, Marcus; Assmann, G.; Mueller-Hoecker, Josef; Franz, Wolfgang-Michael

doi:10.1016/j.exphem.2008.03.014

Cited by 63 publications

(73 citation statements)

References 48 publications

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“…The effects of PTH on hematopoietic progenitors from bone marrow and peripheral blood have been described previously. (20,31) However, to our knowledge, this study is the first to report the effect of PTH on cells in the spleen. We observed a significant increase in the percentage but not the absolute numbers of LKS cells and LT-HSCs on day 7 of PTH treatment.…”

Section: Discussionmentioning

confidence: 79%

Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow

Jacome-Galarza

Lee

Lorenzo

et al. 2010

Journal of Bone and Mineral Research

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Parathyroid hormone (PTH) increases both the number of osteoclast in bone and the number of early hematopoietic stem cells (HSCs) in bone marrow. We previously characterized the phenotype of multiple populations of bone marrow cells with in vitro osteoclastogenic potential in mice. Here we examined whether intermittent administration of PTH influences these osteoclast progenitor (OCP) populations. C57BL/6 mice were treated with daily injections of bPTH(1-34) (80 mg/kg/day) for 7 or 14 days. We found that PTH caused a significant increase in the percentage of TN/CD115 þ CD117 high and TN/CD115 þ CD117 int cells ( p < .05) in bone marrow on day 7. In contrast, PTH decreased the absolute number of TN/CD115 þ CD117 low cells by 39% on day 7 ( p < .05). On day 14, there was no effect of PTH on osteoclast progenitor distribution in vivo. However, PTH treatment for 7 and 14 days did increase receptor activator of NF-kB ligand (RANKL)-and macrophage colony-stimulating factor (M-CSF)-stimulated in vitro osteoclastogenesis and bone resorption in TN/ CD115 þ cells. In the periphery, 14 days of treatment increased the percentage and absolute numbers of HSCs (Lin À CD117 þ Sca-1 þ ) in the spleen ( p < .05). These data correlated with an increase in the percent and absolute numbers of HSCs in bone marrow on day 14 ( p < .05). Interestingly, the effects on hematopoietic progenitors do not depend on osteoclast resorption activity. These results suggest that in vivo PTH treatment increased in vitro osteoclastogenesis and resorption without altering the number of osteoclast precursors. This implies that in vivo PTH induces sustained changes, possibly through an epigenetic mechanism, in the in vitro responsiveness of the cells to M-CSF and RANKL. ß

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Section: Discussionmentioning

confidence: 79%

Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow

Jacome-Galarza

Lee

Lorenzo

et al. 2010

Journal of Bone and Mineral Research

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“…[2][3][4] Although clinical investigations are assessing intermittent PTH administration as a potential stem cell therapy after bone marrow transplants, 5 the mechanisms mediating PTH actions on hematopoiesis are poorly understood.…”

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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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Section: Introductionmentioning

confidence: 99%

“…18 Recently, PTH injections were also shown to increase both HSC mobilization and engraftment in mouse models of BM transplantation. 5,19,20 These studies have led to clinical trials using PTH to enhance HSC-based therapies 21 and raised the exciting possibility of improving HSC function by modulating osteoblast factors, particularly via GPCR signals.The complexity of the G s ␣ gene locus, embryonic lethality of G s ␣ overactivity, and genetic imprinting of this locus pose significant challenges for manipulating G s signaling in vivo. 22 Engineered receptors, such as RASSLs (receptors activated solely by synthetic ligands), are powerful tools for studying GPCR signaling.…”

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confidence: 99%

Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice

Schepers

Hsiao

Garg

et al. 2012

Blood

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IntroductionHematologic malignancies account for ϳ 9% of all newly diagnosed cancers in the United States. 1 Changes in hematopoiesis also occur in many medical conditions and significantly contribute to morbidity and mortality. Although blood disorders arise primarily from defects in hematopoietic cells, contextual signals from stromal cells in the BM microenvironment or "niche" may also influence disease development.Adult hematopoiesis occurs in the BM where multipotent hematopoietic stem cells (HSCs) generate all lineages of mature blood cells through a hierarchy of developmentally restricted progenitor populations. 2 HSCs reside in specialized niches formed by different stromal populations, including endothelial cells (ECs), mesenchymal stem cells (MSCs), and osteoblastic-lineage cells (OBCs), which express key HSC-supportive factors, including Notch ligands, Cxcl12, and angiopoietin-1 (Angpt1). 3,4 Although early mouse studies have implicated mature osteoblasts as important regulators of HSC numbers, 5-7 more recent work has shown that immature OBCs and perivascular MSCs are in fact the major BM niche constituents ensuring HSC maintenance. [8][9][10] Coculture experiments have also demonstrated the functional importance of interactions with ECs and OBCs in regulating blood production by HSCs. 11,12 These findings indicate that ECs, OBCs, and MSCs are 3 essential BM stromal cell populations that regulate HSC activity and blood homeostasis.Recent work has also illustrated how changes in BM stromal cells contribute to the development of hematologic diseases. Genetic ablation of the retinoblastoma, 13 retinoic acid receptor gamma, 14 or miRNA processing enzyme Dicer 15 genes in BM stromal cells or osteoprogenitor cells all resulted in dysfunctional BM niches promoting myeloproliferative neoplasms or myelodysplastic syndromes. Furthermore, the loss of G s G-protein-coupled receptor (GPCR) signaling in osteoprogenitor cells was found to impair B-cell development. 16 These examples stress the role of BM stromal niche cells in regulating hematopoiesis and indicate that appropriate GPCR signals are crucial for normal blood development.Surprisingly little is known about how abnormal G s -GPCR signaling in osteoblastic cells affects hematopoiesis. Activation of the key osteoblast G s GPCR parathyroid hormone receptor 1 (PTHR1) by parathyroid hormone (PTH) causes changes in osteoblast proliferation, differentiation, and function. 17 Clinically, daily injection of recombinant PTH is used to increase bone formation for osteoporosis treatment. 18 Recently, PTH injections were also shown to increase both HSC mobilization and engraftment in mouse models of BM transplantation. 5,19,20 These studies have led to clinical trials using PTH to enhance HSC-based therapies 21 and raised the exciting possibility of improving HSC function by modulating osteoblast factors, particularly via GPCR signals.The complexity of the G s ␣ gene locus, embryonic lethality of G s ␣ overactivity, and genetic imprinting of this locus pose significa...

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Parathyroid hormone effectively induces mobilization of progenitor cells without depletion of bone marrow

Cited by 63 publications

References 48 publications

Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow

Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow

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

Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice

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