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, Cecilia; Persson, Emelie; Baldock, Paul A.; Stenberg, Åsa; Boström, Ingrid M.; Matozaki, Takashi; Oldenborg, Per‐Arne; Lundberg, Pernilla

doi:10.1074/jbc.m113.494591

Cited by 27 publications

(36 citation statements)

References 25 publications

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“…TSP1‐CD47 interactions play a role in the formation of multiple myeloma‐dendritic cell fusions with bone‐resorbing capacity, and TSP1‐CD36 ligation can promote osteoclastic resorption on dentine slices . CD47−/− mice have a bone resorption defect, which we have shown is due to increased iNOS in OCs . Together these data led us to hypothesize that OB‐secreted TSP1 sequestered in bone matrix will modulate OC function thereby coupling OB activity to OC formation.…”

Section: Introductionmentioning

confidence: 63%

“…TSP1 is expressed by OBs and is present in osteoid and mineralized bone matrix, where it is directly deposited by bone‐forming OBs . TSP1 is involved in OB differentiation in part through activation of latent TGF‐β, and TSP1 receptors CD47 and CD36 also regulate OB . TSP1 is a regulator of NO in endothelial cells, platelets, and vascular smooth muscle cells, but only receptors CD36 and CD47 have been implicated in NO regulation .…”

Section: Introductionmentioning

confidence: 99%

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Thrombospondin-1 Regulates Bone Homeostasis Through Effects on Bone Matrix Integrity and Nitric Oxide Signaling in Osteoclasts

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Hurchla

et al. 2014

Journal of Bone and Mineral Research

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Thrombospondin-1 (TSP1), an endogenous antiangiogenic, is a widely expressed secreted ligand with roles in migration, adhesion and proliferation and is a target for new therapeutics. While TSP1 is present in the bone matrix and several TSP1 receptors play roles in bone biology, the role of TSP1 in bone remodeling has not been fully elucidated. Bone turnover is characterized by coordinated activity of bone-forming osteoblasts (OB) and bone-resorbing osteoclasts (OC). TSP1−/− mice had increased bone mass and increased cortical bone size and thickness compared to wild type (WT). However, despite increased size, TSP1−/− femurs showed less resistance to bending than expected, indicative of diminished bone quality and a bone material defect. Additionally, we found that TSP1 deficiency resulted in decreased OC activity in vivo and reduced OC differentiation. TSP1 was critical during early osteoclastogenesis, and TSP1 deficiency resulted in a substantial overexpression of inducible nitric oxide synthase (iNOS). Importantly, administration of a NOS inhibitor rescued the OC function defects of TSP1−/− mice in vivo. To investigate the role of bone-derived TSP1 in osteoclastogenesis, we found that wild type (WT) pre-OCs had defective iNOS expression when cultured on TSP1−/− bone compared to WT bone, suggesting that TSP1 in bone plays a critical role in iNOS signaling during OC development. These data implicate a new role for TSP1 in bone homeostasis with roles in maintaining bone matrix integrity and regulating OC formation. It will be critical to monitor bone health of patients administered TSP1-pathway directed therapeutics in clinical use and under development.

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Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Thrombospondin-1 Regulates Bone Homeostasis Through Effects on Bone Matrix Integrity and Nitric Oxide Signaling in Osteoclasts

Amend

Uluçkan

Hurchla

et al. 2014

Journal of Bone and Mineral Research

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“…In these studies, the total number of OCs with three nuclei or more was analyzed at the end of the culture, but without reporting details on the actual number of nuclei per cell (Lundberg et al, 2007; Maile et al, 2011; Koskinen et al, 2013). In our recent study (Hobolt‐Pedersen et al, 2014), we used a CD47 blocking‐antibody and evaluated at the end of the culture the number of nuclei in all OCs both in control condition as well as in the presence of the blocking antibody.…”

Section: Discussionmentioning

confidence: 99%

“…The most prominent of these is DC‐STAMP (dendritic cell‐specific transmembrane protein) (Kukita et al, 2004; Yagi et al, 2005; Iwasaki et al, 2008; Mensah et al, 2010; Chiu et al, 2012; Chiu and Ritchlin, 2016), which has been identified as one of the most essential single factors supporting both differentiation and fusion. However, also other factors such as CD47 (Han et al, 2000; Lundberg et al, 2007; Maile et al, 2011; Koskinen et al, 2013; Hobolt‐Pedersen et al, 2014), syncytin‐1 (Soe et al, 2011), OC‐STAMP (osteoclast stimulatory transmembrane protein) (Miyamoto et al, 2012; Witwicka et al, 2015), dynamin (Shin et al, 2014; Verma et al, 2014), Pin1 (peptidyl‐prolyl cis‐trans isomerase NIMA‐interacting 1) (Islam et al, 2014; Cho et al, 2015), and e‐cadherin (Mbalaviele et al, 1995; Fiorino and Harrison, 2016) are involved in OC fusion, but it is important to stress that this list is not exhaustive. In order to identify the role of these factors , a series of molecular techniques, and cellular model systems have been employed, which in general are evaluated through end‐point measurements by counting the number of multi‐nucleated OCs, number of nuclei per OC, resorptive activity, and so forth at the end of the incubation period.…”

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confidence: 99%

Osteoclast Fusion: Time‐Lapse Reveals Involvement of CD47 and Syncytin‐1 at Different Stages of Nuclearity

Møller

Delaissé

Søe

2016

Journal Cellular Physiology

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Investigations addressing the molecular keys of osteoclast fusion are primarily based on end‐point analyses. No matter if investigations are performed in vivo or in vitro the impact of a given factor is predominantly analyzed by counting the number of multi‐nucleated cells, the number of nuclei per multinucleated cell or TRAcP activity. But end‐point analyses do not show how the fusion came about. This would not be a problem if fusion of osteoclasts was a random process and occurred by the same molecular mechanism from beginning to end. However, we and others have in the recent period published data suggesting that fusion partners may specifically select each other and that heterogeneity between the partners seems to play a role. Therefore, we set out to directly test the hypothesis that fusion factors have a heterogenic involvement at different stages of nuclearity. Therefore, we have analyzed individual fusion events using time‐lapse and antagonists of CD47 and syncytin‐1. All time‐lapse recordings have been studied by two independent observers. A total of 1808 fusion events were analyzed. The present study shows that CD47 and syncytin‐1 have different roles in osteoclast fusion depending on the nuclearity of fusion partners. While CD47 promotes cell fusions involving mono‐nucleated pre‐osteoclasts, syncytin‐1 promotes fusion of two multi‐nucleated osteoclasts, but also reduces the number of fusions between mono‐nucleated pre‐osteoclasts. Furthermore, CD47 seems to mediate fusion mostly through broad contact surfaces between the partners’ cell membrane while syncytin‐1 mediate fusion through phagocytic‐cup like structure. J. Cell. Physiol. 232: 1396–1403, 2017. © 2016 Wiley Periodicals, Inc.

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“…Blocking antibodies against CD47 and SIRPα also reduced the numbers of TRAP + osteoclasts formed in cultures of murine hematopoietic cells stimulated by M-CSF and RANKL. Further study identified reduced expression of the osteoclastogenic genes nfatc1 , Oscar , Trap/Acp , ctr , catK , and dc-stamp in bone marrow cultures from cd47 −/− mice stimulated with parathyroid hormone or 1α,25(OH) 2 -vitamin D3 (Koskinen et al, 2013). Stromal cells lacking either CD47 or the cytoplasmic tail of SIRPα were defective in supporting osteoclastogenesis in WT bone marrow-derived macrophages.…”

Section: Tsp1-cd47-sirpα Regulation In Bone Developmentmentioning

confidence: 99%

Divergent modulation of normal and neoplastic stem cells by thrombospondin-1 and CD47 signaling

Kaur

Roberts

2016

The International Journal of Biochemistry & Cell Biology

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Thrombospondin-1 is a secreted matricellular protein that regulates the differentiation and function of many cell types. Thrombospondin-1 is not required for embryonic development, but studies using lineage-committed adult stem cells have identified positive and negative effects of thrombospondin-1 on stem cell differentiation and self-renewal and identified several thrombospondin-1 receptors that mediate these responses. Genetic studies in mice reveal a broad inhibitory role of thrombospondin-1 mediated by its receptor CD47. Cells and tissues lacking thrombospondin-1 or CD47 exhibit an increased capacity for self-renewal associated with increased expression of the stem cell transcription factors c-Myc, Sox2, Klf4, and Oct4. Thrombospondin-1 inhibits expression of these transcription factors in a CD47-dependent manner. However, this regulation differs in some neoplastic cells. Tumor initiating/cancer stem cells express high levels of CD47, but in contrast to nontransformed stem cells CD47 signaling supports cancer stem cells. Suppression of CD47 expression in cancer stem cells or ligation of CD47 by function blocking antibodies or thrombospondin-1 results in loss of self-renewal. Therefore, the therapeutic CD47 antagonists that are in clinical development for stimulating innate anti-tumor immunity may also inhibit tumor growth by suppressing cancer stem cells. These and other therapeutic modulators of thrombospondin-1 and CD47 signaling may also have applications in regenerative medicine to enhance the function of normal stem cells.

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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

Cited by 27 publications

References 25 publications

Thrombospondin-1 Regulates Bone Homeostasis Through Effects on Bone Matrix Integrity and Nitric Oxide Signaling in Osteoclasts

Thrombospondin-1 Regulates Bone Homeostasis Through Effects on Bone Matrix Integrity and Nitric Oxide Signaling in Osteoclasts

Osteoclast Fusion: Time‐Lapse Reveals Involvement of CD47 and Syncytin‐1 at Different Stages of Nuclearity

Divergent modulation of normal and neoplastic stem cells by thrombospondin-1 and CD47 signaling

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