Miki Maeda, Hiroaki Saito, Amy B P Ribet, Eric Hesse, Hanna Taipaleenmäki
{"title":"tgif1缺乏通过pp2a介导的ERK1/2去磷酸化损害破骨细胞分化,并减轻小鼠骨质流失。","authors":"Miki Maeda, Hiroaki Saito, Amy B P Ribet, Eric Hesse, Hanna Taipaleenmäki","doi":"10.1093/jbmr/zjaf107","DOIUrl":null,"url":null,"abstract":"<p><p>Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9000,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tgif1-deficiency impairs osteoclast differentiation through PP2A-mediated ERK1/2 dephosphorylation and attenuates bone loss in mice.\",\"authors\":\"Miki Maeda, Hiroaki Saito, Amy B P Ribet, Eric Hesse, Hanna Taipaleenmäki\",\"doi\":\"10.1093/jbmr/zjaf107\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.</p>\",\"PeriodicalId\":185,\"journal\":{\"name\":\"Journal of Bone and Mineral Research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2025-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Bone and Mineral Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/jbmr/zjaf107\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Bone and Mineral Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/jbmr/zjaf107","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Tgif1-deficiency impairs osteoclast differentiation through PP2A-mediated ERK1/2 dephosphorylation and attenuates bone loss in mice.
Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.
期刊介绍:
The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.