A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice

Park, Doori; Park, Chan Won; Choi, Young Jin; Lin, Jingjing; Seo, Dong Han; Kim, Han Sung; Lee, Soo Young; Kang, In Cheol

doi:10.1016/j.biomaterials.2016.05.007

Cited by 34 publications

(24 citation statements)

References 61 publications

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“…During this process, the inflammatory infiltration in the stroma facilitates the alternative splicing of FN gene, generating the isoforms of EDA + FN, EDB + FN, and CS1‐FN (Boyle et al, ; Heikinheimo et al, ; Khan et al, ; Liu et al, ). These isoforms not only directly interact with the receptors in pre‐osteoclast (Park et al, ; Xing et al, ), but also stimulate the secretion of cytokines via autocrine and then induce the osteoclastogenesis indirectly (Gondokaryono et al, ; Khan et al, ; Liu et al, ). In this study, the associations between FN isoforms as well as bone destruction were focused, according to the radiolucent areas which have been demonstrated linearly relate to the size of lesions in odontogenic cysts (Kubota et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…In the conditioned medium, the Trap + MNCs induced by the fibroblasts of cysts were significantly more than that by the controls, consistent with the higher ratio of EDA + FN/total FN in the former. In fact, the number of Trap + MNCs was associated with EDA + FN/total FN in the fibroblasts of cysts positively ( p < 0.05), suggesting its contribution to the osteoclastogenesis; it perhaps relied on the interaction between EDA fragment and receptors in the pre‐osteoclasts, such as the integrin or Toll‐Like Receptors (TLRs; Park et al, ; Xing et al, ). On the other hand, in contrast with the control fibroblasts, the higher expression of COX‐2, IL‐6, IL‐17, and RANKL/OPG perhaps could be attributed to the autocrine effects of EDA + FN on the fibroblasts from cysts.…”

Section: Discussionmentioning

confidence: 99%

“…Although the influence of FN isoforms on the bone destruction remains not very clear, EDA + FN, EDB + FN, or CS1‐FN may interact with receptors in pre‐osteoclasts, such as integrin (Park et al, ) or Toll‐like Receptor 4 (TLR4) (Xing, Vos, Faas, Ye, & Ren, ), suggesting direct paracrine effects on osteoclastogenesis. Additionally, the interactions between FN isoforms and the cells secreting TNF‐α, IL‐6, VEGF or IL‐17 etc (Gondokaryono et al, ; Khan et al, ; Liu et al, ), suggesting additional indirect effects.…”

Section: Introductionmentioning

confidence: 99%

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The fibroblast of radicular cyst facilitate osteoclastogenesis via the autocrine of Fibronectin containing extra domain A

Liu

Wang

2019

Oral Diseases

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Objective To investigate the alternative spliced isoforms of Fibronectin (FN) in the stroma of radicular cysts and analyze the associations between these isoforms and the osteoclastogenic effects of fibroblasts. Methods and materials The specimens of radicular cysts were stained with immunohistochemistry, and the associations between each FN isoform and clinical parameters were assessed. The fibroblasts isolated from cysts or jaw bone were cultured to induce the Trap + MNCs. In the conditioned medium, the Fibronectin containing extra domain A (EDA + FN) was neutralized by antibody IST‐9, and the EDA exon of fibroblasts was knockout by CRISPR/Cas system, for assessing the osteoclastogenic effects. The mRNA level of FN isoforms and the osteoclastogenesis‐related genes were analyzed by quantitive PCR. Results EDA + FN staining was positively associated with the size of the lesions (p < 0.05). In contrast with the controls, the ratio of EDA + FN/total FN in the fibroblasts from radicular cysts was significantly higher (p < 0.05), and positively associate with Trap + MNCs counting, it was consistent with increased expression of COX‐2, IL‐6, IL‐17, and the RANKL/OPG (p < 0.05). The Trap + MNCs counting and osteoclastogenesis‐related genes were decreased by IST‐9 blocking and EDA exon knockout in fibroblasts, but the blockage of the interaction between EDA + FN and pre‐osteoclasts exhibited little effects on Trap + MNCs formation. Conclusion The microenvironment of the fibrous capsule of radicular cysts facilitates the splicing of EDA exon, it endues EDA + FN with autocrine effects on fibroblast itself, and it increases the expression of osteoclastogenesis‐related genes, by which the osteoclastogenesis in radicular cysts could be initiated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The fibroblast of radicular cyst facilitate osteoclastogenesis via the autocrine of Fibronectin containing extra domain A

Liu

Wang

2019

Oral Diseases

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“…In vivo, IPS-02001 blocked RANKL-induced bone destruction and suppressed ovariectomy-induced bone loss. This pioneering work showed that IPS-02001 is a potent inhibitor of integrin-mediated OPN signaling and suggests that it may be used also in cancer [248]. …”

Section: Therapeutic Strategies Targeting Opn In Cancermentioning

confidence: 99%

Osteopontin at the Crossroads of Inflammation and Tumor Progression

Castello

Raineri

Salmi

et al. 2017

Mediators of Inflammation

148

132

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Complex interactions between tumor and host cells regulate systemic tumor dissemination, a process that begins early at the primary tumor site and goes on until tumor cells detach themselves from the tumor mass and start migrating into the blood or lymphatic vessels. Metastatic cells colonize the target organs and are capable of surviving and growing at distant sites. In this context, osteopontin (OPN) appears to be a key determinant of the crosstalk between cancer cells and the host microenvironment, which in turn modulates immune evasion. OPN is overexpressed in several human carcinomas and has been implicated in inflammation, tumor progression, and metastasis. Thus, it represents one of the most attracting targets for cancer therapy. Within the tumor mass, OPN is secreted in various forms either by the tumor itself or by stroma cells, and it can exert either pro- or antitumorigenic effects according to the cell type and tumor microenvironment. Thus, targeting OPN for therapeutic purposes needs to take into account the heterogeneous functions of the multiple OPN forms with regard to cancer formation and progression. In this review, we will describe the role of systemic, tumor-derived, and stroma-derived OPN, highlighting its pivotal role at the crossroads of inflammation and tumor progression.

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“…It contains the wellknown integrin-binding sequence Arg-Gly-Asp (RGD), which mediates binding to many different integrins, including the most important receptor, the α V β 3 -integrin. The OPN integrin interactions initiate and regulate many of the functions propagated by the protein, such as cell adhesion, migration, bone resorption, and immune modulation (Christensen et al, 2012;Kahles et al, 2014;Park et al, 2016;Lok and Lyle, 2019). In addition, OPN contains a second cryptic integrin-binding motif, the SVVYGLR sequence (SVAYGLK in bovine OPN), located next to the RGD sequence (Yokosaki et al, 2005;Christensen et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Milk osteopontin retains integrin-binding activity after in vitro gastrointestinal transit

Christensen

Karlsen

Jørgensen

et al. 2020

Journal of Dairy Science

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Osteopontin (OPN) is a multifunctional protein highly expressed in milk, where it is hypothesized to be involved in immunological signaling via the conserved Arg-Gly-Asp (RGD) integrin-binding sequence. Intervention studies have indicated beneficial effects of orally administered OPN in animal and human infants, but the mechanisms underlying these effects are not well described. To induce physiological effects, OPN must resist gastrointestinal transit in a bioactive form. In this study, we subjected bovine milk OPN to in vitro gastrointestinal transit, and characterized the generated fragments using monoclonal antibody and mass spectrometric analyses. We found that the fragment Trp 27 -Phe 151 containing the integrin-binding RGD sequence resisted in vitro gastric digestion. This resistance was dependent on glycosylation of threonine residues near the integrin-binding sequence in both human and bovine milk OPN. Furthermore, the fragment Trp 27 -Phe 151 retained the ability to interact with integrins in an RGD-dependent process. These results suggest a mechanism for how ingested milk OPN can induce physiological effects via integrin signaling in the intestine.

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A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice

Cited by 34 publications

References 61 publications

The fibroblast of radicular cyst facilitate osteoclastogenesis via the autocrine of Fibronectin containing extra domain A

The fibroblast of radicular cyst facilitate osteoclastogenesis via the autocrine of Fibronectin containing extra domain A

Osteopontin at the Crossroads of Inflammation and Tumor Progression

Milk osteopontin retains integrin-binding activity after in vitro gastrointestinal transit

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