{"doi":"10.1042/bj20040380","title":"Zoledronic acid up-regulates bone sialoprotein expression in osteoblastic cells through Rho GTPase inhibition","abstract":"<jats:p>Clinical practice reveals that osteoporotic women treated with BPs (bisphosphonates) show an increased bone mass density and a reduced risk of fractures. However, the mechanisms leading to these beneficial effects of BPs are still poorly understood. We hypothesized that ZOL (zoledronic acid), a potent third-generation BP, may induce the expression of proteins associated with the bone-forming potential of osteoblastic cells such as BSP (bone sialo-protein). Expression of BSP gene is up-regulated by hormones that promote bone formation and has been associated with de novo bone mineralization. Using real-time reverse transcriptase–PCR and Western-blot analysis, we demonstrated that ZOL increased BSP expression in Saos-2 osteoblast-like cells. Nuclear run-on and mRNA decay assays showed no effect at the transcriptional level but a stabilization of BSP transcripts in ZOL-treated cells. ZOL effect on BSP expression occurred through an interference with the mevalonate pathway since it was reversed by either mevalonate pathway intermediates or a Rho GTPase activator. We showed that ZOL impaired membrane localization of RhoA in Saos-2 cells indicating reduced prenylation of this protein. By the use of small interfering RNAs directed to RhoA and Rac1, we identified both Rho GTPases as negative regulators of BSP expression in Saos-2 cells. Our study demonstrates that ZOL induces BSP expression in osteoblast-like cells through inactivation of Rho GTPases and provides a potential mechanism to explain the favourable effects of ZOL treatment on bone mass and integrity.</jats:p>","journal":"Biochemical Journal","year":2004,"id":604043,"datarank":0.5456379239589579,"base_score":3.6375861597263857,"endowment":3.6375861597263857,"self_citation_contribution":0.5456379239589579,"citation_network_contribution":0.0,"self_endowment_contribution":0.5456379239589579,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1549700,"name":"Cédric DETRY","orcid":null,"position":1,"is_corresponding":false},{"id":1549702,"name":"Christophe DEROANNE","orcid":null,"position":2,"is_corresponding":false},{"id":1549704,"name":"Larry W. FISHER","orcid":null,"position":3,"is_corresponding":false},{"id":1549706,"name":"Vincent CASTRONOVO","orcid":null,"position":4,"is_corresponding":false},{"id":1549708,"name":"Akeila BELLAHCÉNE","orcid":null,"position":5,"is_corresponding":false},{"id":1549698,"name":"Michaël CHAPLET","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Zoledronic acid up-regulates bone sialoprotein expression in osteoblastic cells through Rho GTPase inhibition","abstract":"<jats:p>Clinical practice reveals that osteoporotic women treated with BPs (bisphosphonates) show an increased bone mass density and a reduced risk of fractures. However, the mechanisms leading to these beneficial effects of BPs are still poorly understood. We hypothesized that ZOL (zoledronic acid), a potent third-generation BP, may induce the expression of proteins associated with the bone-forming potential of osteoblastic cells such as BSP (bone sialo-protein). Expression of BSP gene is up-regulated by hormones that promote bone formation and has been associated with de novo bone mineralization. Using real-time reverse transcriptase–PCR and Western-blot analysis, we demonstrated that ZOL increased BSP expression in Saos-2 osteoblast-like cells. Nuclear run-on and mRNA decay assays showed no effect at the transcriptional level but a stabilization of BSP transcripts in ZOL-treated cells. ZOL effect on BSP expression occurred through an interference with the mevalonate pathway since it was reversed by either mevalonate pathway intermediates or a Rho GTPase activator. We showed that ZOL impaired membrane localization of RhoA in Saos-2 cells indicating reduced prenylation of this protein. By the use of small interfering RNAs directed to RhoA and Rac1, we identified both Rho GTPases as negative regulators of BSP expression in Saos-2 cells. Our study demonstrates that ZOL induces BSP expression in osteoblast-like cells through inactivation of Rho GTPases and provides a potential mechanism to explain the favourable effects of ZOL treatment on bone mass and integrity.</jats:p>","is_dataset_classified":null,"base_score":3.6375861597263857,"endowment":3.6375861597263857,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"15324309","pmcid":"PMC1134145","openalex_id":"https://openalex.org/W1971191300","authors":[],"funders":[],"total_grants":0,"fwci":2.0328,"citation_percentile":0.85871614,"influential_citations":0,"citation_trend":[{"year":2012,"count":1},{"year":2013,"count":2},{"year":2015,"count":1},{"year":2016,"count":1},{"year":2017,"count":2},{"year":2022,"count":1},{"year":2023,"count":1},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://portlandpress.com/biochemj/article-pdf/384/3/591/714891/bj3840591.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1042/bj20040380","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/15324309","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/1134145","host_type":"repository"},{"url":"https://orbi.uliege.be/handle/2268/24069","host_type":"repository"}],"fields_of_study":["Bone health and treatments","Bone Metabolism and Diseases","Bone health and osteoporosis research","Calcification, Physiologic","Cell Line, Tumor","Cell Membrane","Cytosol","Diphosphonates","Humans","Imidazoles","Integrin-Binding Sialoprotein","Osteoblasts","Protein Transport","RNA, Messenger","Sialoglycoproteins","Transcription, Genetic","Up-Regulation","Zoledronic Acid","rac1 GTP-Binding Protein","rhoA GTP-Binding Protein"],"mesh_terms":["Zoledronic Acid","Calcification, Physiologic","Cell Membrane","Cytosol","Diphosphonates","Humans","Imidazoles","Osteoblasts","RNA, Messenger","Sialoglycoproteins","Transcription, Genetic","Up-Regulation","rhoA GTP-Binding Protein","rac1 GTP-Binding Protein","Protein Transport","Cell Line, Tumor","Integrin-Binding Sialoprotein"],"keywords":["RHOA","Bone sialoprotein","Osteoblast","RAC1","Chemistry","Cell biology","Small GTPase","Activator (genetics)","Prenylation","Small interfering RNA","Mevalonate pathway","Western blot","RUNX2","Internal medicine","Molecular biology","Endocrinology","Cancer research","Osteocalcin","Biology","Signal transduction","Alkaline phosphatase","Biochemistry","Transfection","Medicine","Gene","Biosynthesis"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T23:15:23.443574Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}