Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis
Bone metastasis (BM) is a dismal complication of cancer that frequently occurs in patients with advanced carcinomas and that often manifests as an osteolytic lesion. In bone, tumor cells promote an imbalance in bone remodeling via the release of growth factors that, directly or indirectly, stimulate...
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.678532/full |
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| author | Gemma Di Pompo Costantino Errani Robert Gillies Laura Mercatali Toni Ibrahim Jacopo Tamanti Nicola Baldini Nicola Baldini Sofia Avnet Sofia Avnet |
| author_facet | Gemma Di Pompo Costantino Errani Robert Gillies Laura Mercatali Toni Ibrahim Jacopo Tamanti Nicola Baldini Nicola Baldini Sofia Avnet Sofia Avnet |
| author_sort | Gemma Di Pompo |
| collection | DOAJ |
| description | Bone metastasis (BM) is a dismal complication of cancer that frequently occurs in patients with advanced carcinomas and that often manifests as an osteolytic lesion. In bone, tumor cells promote an imbalance in bone remodeling via the release of growth factors that, directly or indirectly, stimulate osteoclast resorption activity. However, carcinoma cells are also characterized by an altered metabolism responsible for a decrease of extracellular pH, which, in turn, directly intensifies osteoclast bone erosion. Here, we speculated that tumor-derived acidosis causes the osteoblast–osteoclast uncoupling in BM by modulating the pro-osteoclastogenic phenotype of osteoblasts. According to our results, a low pH recruits osteoclast precursors and promotes their differentiation through the secretome of acid-stressed osteoblasts that includes pro-osteoclastogenic factors and inflammatory mediators, such as RANKL, M-CSF, TNF, IL-6, and, above the others, IL-8. The treatment with the anti-IL-6R antibody tocilizumab or with an anti-IL-8 antibody reverted this effect. Finally, in a series of BM patients, circulating levels of the osteolytic marker TRACP5b significantly correlated with IL-8. Our findings brought out that tumor-derived acidosis promotes excessive osteolysis at least in part by inducing an inflammatory phenotype in osteoblasts, and these results strengthen the use of anti-IL-6 or anti-IL-8 strategies to treat osteolysis in BM. |
| first_indexed | 2024-12-17T00:39:02Z |
| format | Article |
| id | doaj.art-22adb51a329f4ab8864534961bda888d |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T00:39:02Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-22adb51a329f4ab8864534961bda888d2022-12-21T22:10:04ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-05-01910.3389/fcell.2021.678532678532Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone MetastasisGemma Di Pompo0Costantino Errani1Robert Gillies2Laura Mercatali3Toni Ibrahim4Jacopo Tamanti5Nicola Baldini6Nicola Baldini7Sofia Avnet8Sofia Avnet9Biomedical Science and Technologies Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, ItalyOrthopaedic Oncology Surgical Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, ItalyDepartment of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United StatesOsteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyOsteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyNational Tumor Assistance (ANT) Foundation, Bologna, ItalyBiomedical Science and Technologies Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyBiomedical Science and Technologies Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyBone metastasis (BM) is a dismal complication of cancer that frequently occurs in patients with advanced carcinomas and that often manifests as an osteolytic lesion. In bone, tumor cells promote an imbalance in bone remodeling via the release of growth factors that, directly or indirectly, stimulate osteoclast resorption activity. However, carcinoma cells are also characterized by an altered metabolism responsible for a decrease of extracellular pH, which, in turn, directly intensifies osteoclast bone erosion. Here, we speculated that tumor-derived acidosis causes the osteoblast–osteoclast uncoupling in BM by modulating the pro-osteoclastogenic phenotype of osteoblasts. According to our results, a low pH recruits osteoclast precursors and promotes their differentiation through the secretome of acid-stressed osteoblasts that includes pro-osteoclastogenic factors and inflammatory mediators, such as RANKL, M-CSF, TNF, IL-6, and, above the others, IL-8. The treatment with the anti-IL-6R antibody tocilizumab or with an anti-IL-8 antibody reverted this effect. Finally, in a series of BM patients, circulating levels of the osteolytic marker TRACP5b significantly correlated with IL-8. Our findings brought out that tumor-derived acidosis promotes excessive osteolysis at least in part by inducing an inflammatory phenotype in osteoblasts, and these results strengthen the use of anti-IL-6 or anti-IL-8 strategies to treat osteolysis in BM.https://www.frontiersin.org/articles/10.3389/fcell.2021.678532/fullbone metastasisintratumoral acidosisosteoclastsosteoblastsinterleukin 8interleukin 6 |
| spellingShingle | Gemma Di Pompo Costantino Errani Robert Gillies Laura Mercatali Toni Ibrahim Jacopo Tamanti Nicola Baldini Nicola Baldini Sofia Avnet Sofia Avnet Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis Frontiers in Cell and Developmental Biology bone metastasis intratumoral acidosis osteoclasts osteoblasts interleukin 8 interleukin 6 |
| title | Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis |
| title_full | Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis |
| title_fullStr | Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis |
| title_full_unstemmed | Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis |
| title_short | Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis |
| title_sort | acid induced inflammatory cytokines in osteoblasts a guided path to osteolysis in bone metastasis |
| topic | bone metastasis intratumoral acidosis osteoclasts osteoblasts interleukin 8 interleukin 6 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.678532/full |
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