In vitro osteoclast generation from different bone marrow fractions, including a highly enriched haematopoietic stem cell population

Scheven, Ben A.; Visser, J. W. M.; Nijweide, Peter J.

doi:10.1038/321079a0

Cited by 247 publications

(108 citation statements)

References 11 publications

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“…[2][3][4][5][6]34 Regardless of the precise origin of OCL progenitors, it is clear that any disruption of hematopoiesis can profoundly affect OCL numbers. In the current study we found that an IMiD of thalidomide (CC-4047) inhibits the generation and differentiation of OCLs by down-regulation of PU.1, resulting in a shift of lineage commitment of hematopoietic progenitors.…”

Section: Discussionmentioning

confidence: 99%

“…OCLs are multinucleated cells that derive from monocyte/macrophage lineage cells. [2][3][4][5][6] How commitment to a given lineage occurs among macrophages, OCLs, and dendritic cells has not been fully elucidated, but complex signaling mechanisms are known to control OCL differentiation. 7 These signals include cytokines such as macrophage colony-stimulating factor (CSF-M), granulocytemacrophage colony-stimulating factor (CSF-GM), and interleukin-3, 8 which are macrophage-inducing cytokines, and the receptor activator of NF-B ligand (RANKL), which is a critical factor for late stages of OCL development.…”

Section: Introductionmentioning

confidence: 99%

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Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1

Anderson

Gries

Kurihara

et al. 2006

Blood

144

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IntroductionThe major source of morbidity and possible mortality associated with multiple myeloma (MM) is osteolytic bone destruction throughout the axial skeleton. Lytic bone lesions occur in 70% to 80% of these patients, and are frequently associated with severe bone pain and pathologic fractures. 1 Besides MM, osteolytic lesions also occur in connection with bone metastases from solid tumors. Although the exact incidence of bone metastases is unknown, it is estimated that 350 000 people die with bone metastases each year in the United States. 1 Osteolytic lesions represent an extreme of a continuum of dysregulation of the normal bone remodeling process with excessive bone resorption mediated by osteoclasts (OCLs). OCLs are multinucleated cells that derive from monocyte/macrophage lineage cells. [2][3][4][5][6] How commitment to a given lineage occurs among macrophages, OCLs, and dendritic cells has not been fully elucidated, but complex signaling mechanisms are known to control OCL differentiation. 7 These signals include cytokines such as macrophage colony-stimulating factor (CSF-M), granulocytemacrophage colony-stimulating factor (CSF-GM), and interleukin-3, 8 which are macrophage-inducing cytokines, and the receptor activator of NF-B ligand (RANKL), which is a critical factor for late stages of OCL development. 9 In addition to cytokines, several transcription factors are vital for OCL formation; the most important are PU.1 10 and c-fos. 11,12 PU.1 (Spi-1) is essential for the development of myeloid and B-lymphoid cells. [13][14][15] In myeloid cells, PU.1 is known to regulate transcription of both c-fms and CD11b/CD18 (Mac1), both of which are central to the OCL phenotype. 16-18 PU.1-deficient mice show a failure in macrophage differentiation, and osteoclastogenesis is inhibited at a very early stage of differentiation. 10,19 Mice deficient in c-fos exhibit osteopetrosis due to an OCL differentiation defect, while the number of macrophages increases, indicating that c-fos acts on a later stage of OCL development. 10,11 It is clear that any disruption of hematopoiesis can profoundly affect OCL numbers.Thalidomide was originally developed in the 1950s to treat pregnancy-induced morning sickness. Following the discovery of its teratogenic effects, it was subsequently withdrawn from the market in 1961. 20 Since the discovery of thalidomide's antimyeloma activity in the late 1990s, 21 new and more potent immunomodulatory derivatives (IMiDs) of thalidomide such as CC-4047 (Actimid) and CC-5013 (Revlimid) with fewer side effects have been developed. In previous studies, we showed that IMiDs inhibit For personal use only. on May 10, 2018. by guest www.bloodjournal.org From the in vitro and in vivo growth of MM cells. 22,23 In initial clinical phase 1 and 2 trials, single agent CC-4047 and CC-5013 in combination with dexamethasone achieved response rates of over 50% in relapsed and refractory MM. [24][25][26] We have shown that CC-4047 induces a shift in lineage commitment, resulting in increased myeloid cell deve...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1

Anderson

Gries

Kurihara

et al. 2006

Blood

144

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“…The distribution of these receptors in bone cells does not vary by gender, as similar levels of ER and AR have been found in bone cells from males and females (Benz et al, 1991a,b;Braidman et al, 2000). However, in spite of the demonstration of receptors, convincing evidence that estrogens or androgens modulate the biosynthetic activity of osteoblasts and osteoclasts in a manner that can explain the welldocumented skeletal effects of estrogen loss in vivo remained elusive until the critical role of the bone marrow in bone remodeling was appreciated about a decade ago (Scheven et al, 1986;Kurihara et al, 1989).…”

Section: Effects Of Sex Steroids On Osteoclastogenesismentioning

confidence: 99%

Sex Steroids and Bone

Kousteni²,

Rl³

2002

Recent Progress in Hormone Research

464

313

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The adult skeleton is periodically remodeled by temporary anatomic structures that comprise juxtaposed osteoclast and osteoblast teams and replace old bone with new. Estrogens and androgens slow the rate of bone remodeling and protect against bone loss. Conversely, loss of estrogen leads to increased rate of remodeling and tilts the balance between bone resorption and formation in favor of the former. Studies from our group during the last 10 years have elucidated that estrogens and androgens decrease the number of remodeling cycles by attenuating the birth rate of osteoclasts and osteoblasts from their respective progenitors. These effects result, in part, from the transcriptional regulation of genes responsible for osteoclastogenesis and mesenchymal cell replication and/or differentiation and are exerted through interactions of the ligand-activated receptors with other transcription factors. However, increased remodeling alone cannot explain why loss of sex steroids tilts the balance of resorption and formation in favor of the former. Estrogens and androgens also exert effects on the lifespan of mature bone cells: pro-apoptotic effects on osteoclasts but anti-apoptotic effects on osteoblasts and osteocytes. These latter effects stem from a heretofore unexpected function of the classical "nuclear" sex steroid receptors outside the nucleus and result from activation of a Src/Shc/extracellular signal-regulated kinase signal transduction pathway probably within preassembled scaffolds called caveolae. Strikingly, estrogen receptor (ER) alpha or beta or the androgen receptor can transmit anti-apoptotic signals with similar efficiency, irrespective of whether the ligand is an estrogen or an androgen. More importantly, these nongenotropic, sex-nonspecific actions are mediated by the ligand-binding domain of the receptor and can be functionally dissociated from transcriptional activity with synthetic ligands. Taken together, these lines of evidence strongly suggest that, in sex steroid deficiency, loss of transcriptional effects may be responsible for the increased osteoclastogenesis and osteoblastogenesis and thereby the increased rate of bone remodeling. Loss of nongenotropic anti-apoptotic effects on mature osteoblasts and osteocytes, in combination with an opposite effect on the lifespan of mature osteoclasts, may be responsible for the imbalance between formation and resorption and the progressive loss of bone mass and strength. Elucidation of the dual function of sex steroid receptors has important pathophysiologic and pharmacologic implications. Specifically, synthetic ligands of the ER that can evoke the nongenotropic but not the genotropic signal may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are antiresorptive agents. The same ligands may also circumvent the side effects associated with conventional hormone replacement therapy. 385

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“…Early studies had demonstrated that OCPs originate from the haematopoietic stem cells (Sheven et al, 1986;Hagenaars et al, 1989;Hattersley & Chambers, 1989;Kurihara et al, 1989;Matayoshi et al, 1996) and circulate in PB (Walker, 1973(Walker, , 1975Kahn & Simmons, 1975;Coccia et al, 1980;Faust et al, 1999;. However, whether OCPs possess surface characteristics that distinguish them from other PBMCs (in particular monocytes) is not known.…”

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confidence: 99%

Characterization of osteoclast precursors in human blood

Shalhoub¹,

Elliott

Chiu

et al. 2000

Br J Haematol

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Osteoclast precursors (OCPs) circulate in the mononuclear fraction of peripheral blood (PB), but their abundance and surface characteristics are unknown. Previous studies suggest that the receptor activator for NF‐κB (RANK) on cytokine‐treated OCPs in mouse bone marrow interacts with osteoprotegerin ligand (OPGL/TRANCE/RANKL/ODF) to initiate osteoclast differentiation. Hence, we used a fluorescent form of human OPGL (Hu‐OPGL‐F) to identify possible RANK‐expressing OCPs in untreated peripheral blood mononuclear cells (PBMCs) using fluorescence‐activated cell sorting analysis. Monocytes [CD14‐phycoerythrin (PE) antibody (Ab) positive (+) cells, 10–15% of PBMCs] all (98–100%) co‐labelled with Hu‐OPGL‐F (n > 18). T lymphocytes (CD3‐PE Ab+ cells, 66% of PBMCs) did not bind Hu‐OPGL‐F; however, B cells (CD19‐PE Ab+ cells, 9% of PBMCs) were also positive for Hu‐OPGL‐F. All Hu‐OPGL‐F+ monocytes also co‐labelled with CD33, CD61, CD11b, CD38, CD45 and CD54 Abs, but not CD34 or CD56 Abs. Hu‐OPGL‐F binding was dose dependent and competed with excess Hu‐OPGL. When Hu‐OPGL‐F+, CD14‐PE Ab+, CD33‐PE Ab+, Hu‐OPGL‐F+/CD14‐PE Ab+ or Hu‐OPGL‐F+/CD33‐PE Ab+ cells were cultured with OPGL (20 ng/ml) and colony‐stimulating factor (CSF)‐1 (25 ng/ml), OC‐like cells readily developed. Thus, all freshly isolated monocytes demonstrate displaceable Hu‐OPGL‐F binding, suggesting the presence of RANK on OCPs in PB; also, OCPs within a purified PB monocyte population form osteoclast‐like cells in the complete absence of other cell types in OPGL and CSF‐1 containing medium.

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In vitro osteoclast generation from different bone marrow fractions, including a highly enriched haematopoietic stem cell population

Cited by 247 publications

References 11 publications

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1

Sex Steroids and Bone

Characterization of osteoclast precursors in human blood

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