Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruption
Aims: The physiological function of sclerostin remains unknown. Sclerostin is synthesized by osteocytes and operates by inhibiting the Wnt/β-catenin pathway. Similarly, it is well established that low levels of sclerostin lead to enhanced bone formation and reduced calciuria, and that high levels o...
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The British Editorial Society of Bone & Joint Surgery
2025-05-01
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| Series: | Bone & Joint Research |
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| Online Access: | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.145.BJR-2024-0227.R1 |
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| author | María Encarnacion Rodríguez-Ortiz Juan Miguel Díaz-Tocados Ana Isabel Torralbo Karen Valdés-Díaz Antonio Rivas-Domínguez Fátima Guerrero Irene Reina-Alfonso Manuel Naves-Díaz Cristina Alonso-Montes Cristian Rodelo-Haad Mariano Rodríguez Juan Rafael Muñoz-Castañeda IMIBIC Nephrology Group |
| author_facet | María Encarnacion Rodríguez-Ortiz Juan Miguel Díaz-Tocados Ana Isabel Torralbo Karen Valdés-Díaz Antonio Rivas-Domínguez Fátima Guerrero Irene Reina-Alfonso Manuel Naves-Díaz Cristina Alonso-Montes Cristian Rodelo-Haad Mariano Rodríguez Juan Rafael Muñoz-Castañeda IMIBIC Nephrology Group |
| author_sort | María Encarnacion Rodríguez-Ortiz |
| collection | DOAJ |
| description | Aims: The physiological function of sclerostin remains unknown. Sclerostin is synthesized by osteocytes and operates by inhibiting the Wnt/β-catenin pathway. Similarly, it is well established that low levels of sclerostin lead to enhanced bone formation and reduced calciuria, and that high levels of sclerostin are associated with osteoporosis. Methods: The impact of high levels of recombinant sclerostin on bone and mineral metabolism parameters was analyzed in this study. In male healthy rats, the effects of three elevated doses of sclerostin over a 14-day period were studied, involving bone histomorphometry, micro-CT (μCT), immunohistochemistry, and analysis of mineral metabolism parameters. Results: Although there was increased bone formation, high doses of sclerostin led to a higher reduction in trabecular bone volume due to a significant increase in bone resorption through the direct activation of osteoclastogenesis. In vitro, sclerostin promoted the differentiation of bone marrow stem cells into osteoclasts. Bone resorption, as measured by tartrate-resistant acid phosphatase (TRAP) activity, was excessive in trabecular, cortical, and subchondral bone. Similarly, high doses of sclerostin increased the number of hypertrophic chondrocytes, consequently expanding the growth plate area. At the cortical level, positive TRAP staining could be observed, suggestive of osteocytic osteolysis and trabecularization of cortical bone. The increased bone resorption resulted in a substantial rise in the urinary excretion of phosphorus and calcium, accompanied by elevated levels of FGF23 and a significant decrease in parathyroid hormone (PTH). Conclusion: These findings suggest that elevated levels of sclerostin promote bone resorption through the activation of osteoclasts and the generation of osteocytic osteolysis, resulting in increased calciuria, phosphaturia, and changes in mineral metabolism. Cite this article: Bone Joint Res 2025;14(5):448–462. |
| format | Article |
| id | doaj-art-cf03f0b805484da1a9d32cd11705a314 |
| institution | Kabale University |
| issn | 2046-3758 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | The British Editorial Society of Bone & Joint Surgery |
| record_format | Article |
| series | Bone & Joint Research |
| spelling | doaj-art-cf03f0b805484da1a9d32cd11705a3142025-08-20T03:46:00ZengThe British Editorial Society of Bone & Joint SurgeryBone & Joint Research2046-37582025-05-0114544846210.1302/2046-3758.145.BJR-2024-0227.R1Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruptionMaría Encarnacion Rodríguez-Ortiz0Juan Miguel Díaz-Tocados1Ana Isabel Torralbo2Karen Valdés-Díaz3Antonio Rivas-Domínguez4Fátima Guerrero5Irene Reina-Alfonso6Manuel Naves-Díaz7Cristina Alonso-Montes8Cristian Rodelo-Haad9Mariano Rodríguez10Juan Rafael Muñoz-Castañeda11IMIBIC Nephrology Group Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain Aims: The physiological function of sclerostin remains unknown. Sclerostin is synthesized by osteocytes and operates by inhibiting the Wnt/β-catenin pathway. Similarly, it is well established that low levels of sclerostin lead to enhanced bone formation and reduced calciuria, and that high levels of sclerostin are associated with osteoporosis. Methods: The impact of high levels of recombinant sclerostin on bone and mineral metabolism parameters was analyzed in this study. In male healthy rats, the effects of three elevated doses of sclerostin over a 14-day period were studied, involving bone histomorphometry, micro-CT (μCT), immunohistochemistry, and analysis of mineral metabolism parameters. Results: Although there was increased bone formation, high doses of sclerostin led to a higher reduction in trabecular bone volume due to a significant increase in bone resorption through the direct activation of osteoclastogenesis. In vitro, sclerostin promoted the differentiation of bone marrow stem cells into osteoclasts. Bone resorption, as measured by tartrate-resistant acid phosphatase (TRAP) activity, was excessive in trabecular, cortical, and subchondral bone. Similarly, high doses of sclerostin increased the number of hypertrophic chondrocytes, consequently expanding the growth plate area. At the cortical level, positive TRAP staining could be observed, suggestive of osteocytic osteolysis and trabecularization of cortical bone. The increased bone resorption resulted in a substantial rise in the urinary excretion of phosphorus and calcium, accompanied by elevated levels of FGF23 and a significant decrease in parathyroid hormone (PTH). Conclusion: These findings suggest that elevated levels of sclerostin promote bone resorption through the activation of osteoclasts and the generation of osteocytic osteolysis, resulting in increased calciuria, phosphaturia, and changes in mineral metabolism. Cite this article: Bone Joint Res 2025;14(5):448–462.https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.145.BJR-2024-0227.R1sclerostinbone resorptionbone turnovermineral metabolismtrap activityrat modeltrap-stainingosteoclastscortical bonetrabecular bonechondrocytescalciumgrowth plateosteocytes |
| spellingShingle | María Encarnacion Rodríguez-Ortiz Juan Miguel Díaz-Tocados Ana Isabel Torralbo Karen Valdés-Díaz Antonio Rivas-Domínguez Fátima Guerrero Irene Reina-Alfonso Manuel Naves-Díaz Cristina Alonso-Montes Cristian Rodelo-Haad Mariano Rodríguez Juan Rafael Muñoz-Castañeda IMIBIC Nephrology Group Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruption Bone & Joint Research sclerostin bone resorption bone turnover mineral metabolism trap activity rat model trap-staining osteoclasts cortical bone trabecular bone chondrocytes calcium growth plate osteocytes |
| title | Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruption |
| title_full | Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruption |
| title_fullStr | Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruption |
| title_full_unstemmed | Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruption |
| title_short | Impact of elevated sclerostin levels on bone resorption: unravelling structural changes and mineral metabolism disruption |
| title_sort | impact of elevated sclerostin levels on bone resorption unravelling structural changes and mineral metabolism disruption |
| topic | sclerostin bone resorption bone turnover mineral metabolism trap activity rat model trap-staining osteoclasts cortical bone trabecular bone chondrocytes calcium growth plate osteocytes |
| url | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.145.BJR-2024-0227.R1 |
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