CD47 Regulates Bone Mass and Tumor Metastasis to Bone

Uluçkan, Özge; Becker, Stephanie N.; Deng, Hongju; Zou, Wei; Prior, Julie L.; Piwnica‐Worms, David; Frazier, William A.; Weilbaecher, Katherine N.

doi:10.1158/0008-5472.can-08-3358

Cited by 71 publications

(79 citation statements)

References 53 publications

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“…Our bone phenotype data in CD47 Ϫ/Ϫ mice, on the Balb/c background, are in part confirmed by data from C57BL/6 CD47 Ϫ/Ϫ mice where an osteopenic bone phenotype was demonstrated (14). Although lack of CD47 was not associated with a reduced number of osteoclasts in the bones of C57BL/6 mice, which could possibly be explained by strain differences (13,14). Van Beek et al (24) showed that the SIRP␣ mutant mice had a decreased cortical bone volume, suggested to be due to an increased bone resorbing activity of osteoclasts lacking SIRP␣.…”

Section: Discussionsupporting

confidence: 85%

“…These findings have been confirmed in vitro both by Uluçkan et al (13) and Maile et al (14). However, Maile et al did not find any reduction in number of osteoclasts in vivo (14).…”

supporting

confidence: 66%

“…The authors suggested that the physical interaction between CD47 and SIRP␣ induced SIRP␣ tyrosine phosphorylation, recruitment of SHP-1, and subsequent dephosphorylation of non-muscle cell myosin IIA, which, altogether, would be important to promote fusion and formation of osteoclasts (14). It is hard to interpret these data because the osteoclast formation was driven by addition of exogenous M-CSF and RANKL to the crude bone marrow culture, which based on data from the present study and that of a previous study (13) can compensate for the lack of CD47. The reason why Maile et al (14) only detected late fusion defects when CD47 was missing in the cultures could be that the early osteoclast precursors proliferated and differentiated in the presence of M-CSF.…”

Section: Discussionmentioning

confidence: 46%

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Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein α (SIRPα) Signaling

Koskinen

Persson

Baldock

et al. 2013

Journal of Biological Chemistry

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Background: CD47 and its receptor SIRP␣ are suggested to regulate bone metabolism. Results: Lack of CD47 prevents stromal cell SIRP␣ signaling, which impairs bone marrow stromal cell differentiation, subsequent osteoclast differentiation, and bone homeostasis. Conclusion: CD47 and SIRP␣ both mediate normal bone cell and bone tissue formation. Significance: CD47/SIRP␣ may be a future molecular target to modulate bone homeostasis.

show abstract

Section: Discussionsupporting

confidence: 85%

“…These findings have been confirmed in vitro both by Uluçkan et al (13) and Maile et al (14). However, Maile et al did not find any reduction in number of osteoclasts in vivo (14).…”

supporting

confidence: 66%

Section: Discussionmentioning

confidence: 46%

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Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein α (SIRPα) Signaling

Koskinen

Persson

Baldock

et al. 2013

Journal of Biological Chemistry

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“…To generate primary BMMs, whole BM was extracted from the femurs and tibias of mice and plated in petri dishes in α-MEM medium containing 10% fetal bovine serum and M-CSF-containing CMG-14-12 cell culture supernatant (50 ng/ml). For OC differentiation assays, BMMs were plated at 2 × 10 4 per well in 48-well cell culture plates and fed daily with osteoclastogeneic medium (α-MEM containing 10% FBS, CMG-14-12 supernatant [50 ng/ml], and GST-RANKL [50 ng/ml]) for 3 to 6 days, as previously described (77). Then, 1 μM ADP (Sigma-Aldrich) was added daily to cultures as indicated.…”

Section: Methodsmentioning

confidence: 99%

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

Su¹,

Floyd²,

Hughes³

et al. 2012

J. Clin. Invest.

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104

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The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12 -/-OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12 -/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent α IIb β 3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β 3 gene knockout (Itgb3 -/-) OCs, but its effects were substantially blunted in P2ry12 -/-OCs. In vivo, P2ry12 -/-mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss. IntroductionOsteoclasts (OCs) are multinucleated myeloid lineage cells that are the principal source of bone resorptive activity (1). Enhanced OC activity, bone loss, and fractures are associated with rheumatoid arthritis, postmenopausal osteoporosis, and bone metastases (2). Modulation of osteoclastic bone resorption represents an attractive point of therapeutic intervention for the treatment of such conditions.Numerous purinergic G-protein-coupled nucleotide receptors are expressed in the bone microenvironment (3, 4). For example, uridine diphosphate-activated (UDP-activated) P2Y6 has been reported to increase NF-κB activation and OC survival (5), while P2Y2 (an ATP receptor) expression on osteoblasts (OBs) blocks bone mineralization (6, 7). Hoebertz et al. demonstrated that extracellular adenosine diphosphate (ADP) stimulates OC bone resorption in vitro, in part through the ADP receptor P2Y1 on OC (8); however, other ADP receptors, including purinergic receptor P2Y, G protein coupled, 12 (P2RY12), which is the target of the widely prescribed antiplatelet drug clopidogrel (Plavix), have not been evaluated for their roles in osteoclastic bone resorption.

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“…CD47 not only helps the tumor to prevent phagocytosis but also aid the tumor in its growth, dissemination, metastasis and poor clinical outcome [14,35].…”

Section: Cd47 and Egfrviii-a Good Scaffold For Ptdsermentioning

confidence: 99%

Masking Anti-Phagocytic Signal of Tumor by Pro-Phagocytic Signal-a Key to Immurement of Cancer Cell

Mickymaray

Gurusamy

Natarajan

2016

Int J Pharm Pharm Sci

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Immune surveillance is a mechanism where cells and tissues are watched constantly by ever alerted immune system. Most incipient cancer cells are recognized and eliminated by the immune surveillance mechanism, but still tumors have the ability to evade immune surveillance and immunological killing. One greater arm that tumor use to evade immune surveillance, is by expressing anti-phagocytic signal (CD47). Here we present a provocative hypothesis where cancer cells are removed alive by phagocytic cell (DC). That in turn will elicit effective and higher immunogenic condition. All this could be possible by addition pro-phagocytic signal (PtdSer) over cancer cell surface (Breast Cancer), that mask the presence of anti-phagocytic signal (CD47). In other words, adding eat me signal (PtdSer) over the breast cancer cell surface that mask the presence of don't eat me signal or anti-phagocytic signal present in breast cancer cell surface. This could be possible by using bi-specific antibody, conjugated to PEG-modified liposomes, which carry (PtdSer) pro-phagocytic signal (or) eat me signal, which target both CD47 and EGFRVIII on breast carcinoma. The simultaneous masking of anti-phagocytic signal, and adding of pro-phagocytic signal over cancer cell, will enhance the phagocytic clearance of live tumor cell and elicit immunological killing.

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CD47 Regulates Bone Mass and Tumor Metastasis to Bone

Cited by 71 publications

References 53 publications

Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein α (SIRPα) Signaling

Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein α (SIRPα) Signaling

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

Masking Anti-Phagocytic Signal of Tumor by Pro-Phagocytic Signal-a Key to Immurement of Cancer Cell

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