Hao Luo, Sijian Lin, Jiachao Xiong, Wen Tan, Hao Lv, Zhiming Liu, Qin Wu, Junlong Zhong, Kai Cao
{"title":"card14介导的MYC相互作用促进青少年特发性脊柱侧凸的破骨细胞发生和骨密度降低。","authors":"Hao Luo, Sijian Lin, Jiachao Xiong, Wen Tan, Hao Lv, Zhiming Liu, Qin Wu, Junlong Zhong, Kai Cao","doi":"10.1093/jbmr/zjaf127","DOIUrl":null,"url":null,"abstract":"<p><p>Adolescent idiopathic scoliosis (AIS) is characterized by decreased bone mineral density (BMD), which is associated with an increased risk of skeletal fragility and poor long-term outcomes. This study explores the role of the CARD14 gene in osteoclast differentiation and its contribution to bone metabolism dysregulation in AIS patients. RNA sequencing of peripheral blood mononuclear cells (PBMCs) from AIS patients identified significantly elevated CARD14 expression compared to controls. Functional in vitro assays demonstrated enhanced osteoclastogenesis in PBMC-derived cells from AIS patients, as evidenced by an increase in TRAP-positive multinucleated cells and resorption pit formation. To further elucidate CARD14's role, adenoviral vectors were constructed to overexpress CARD14 in bone marrow-derived macrophages (BMMs) from C57/B6 mice, leading to markedly increased osteoclast differentiation and activity. Next, we utilized bone marrow-specific Card14 knockout mice to investigate the in vivo role of CARD14. These mice exhibited reduced osteoclast activity, improved trabecular bone microarchitecture, and increased BMD, as evidenced by micro-CT and histological analyses. Additionally, serum biomarkers of bone metabolism further corroborated these findings. Mechanistically, CARD14 was found to interact with MYC and regulate osteoclast differentiation through a MYC-dependent pathway, while simultaneously activating NF-κB and MAPK signaling, which are critical for osteoclastogenesis. AIS patients consistently showed lower BMD and higher osteoclast counts than age-matched controls, establishing a link between abnormal osteoclast function and bone loss in AIS. The results highlight that elevated CARD14 expression promotes osteoclastogenesis and bone resorption, contributing to reduced BMD in AIS. Targeting CARD14 and its associated signaling pathways may represent a novel therapeutic approach to address bone density loss in AIS patients, potentially improving their skeletal health and quality of life.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9000,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CARD14-Mediated MYC Interaction Promotes Osteoclastogenesis and Bone Density Reduction in Adolescent Idiopathic Scoliosis.\",\"authors\":\"Hao Luo, Sijian Lin, Jiachao Xiong, Wen Tan, Hao Lv, Zhiming Liu, Qin Wu, Junlong Zhong, Kai Cao\",\"doi\":\"10.1093/jbmr/zjaf127\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Adolescent idiopathic scoliosis (AIS) is characterized by decreased bone mineral density (BMD), which is associated with an increased risk of skeletal fragility and poor long-term outcomes. This study explores the role of the CARD14 gene in osteoclast differentiation and its contribution to bone metabolism dysregulation in AIS patients. RNA sequencing of peripheral blood mononuclear cells (PBMCs) from AIS patients identified significantly elevated CARD14 expression compared to controls. Functional in vitro assays demonstrated enhanced osteoclastogenesis in PBMC-derived cells from AIS patients, as evidenced by an increase in TRAP-positive multinucleated cells and resorption pit formation. To further elucidate CARD14's role, adenoviral vectors were constructed to overexpress CARD14 in bone marrow-derived macrophages (BMMs) from C57/B6 mice, leading to markedly increased osteoclast differentiation and activity. Next, we utilized bone marrow-specific Card14 knockout mice to investigate the in vivo role of CARD14. These mice exhibited reduced osteoclast activity, improved trabecular bone microarchitecture, and increased BMD, as evidenced by micro-CT and histological analyses. Additionally, serum biomarkers of bone metabolism further corroborated these findings. Mechanistically, CARD14 was found to interact with MYC and regulate osteoclast differentiation through a MYC-dependent pathway, while simultaneously activating NF-κB and MAPK signaling, which are critical for osteoclastogenesis. AIS patients consistently showed lower BMD and higher osteoclast counts than age-matched controls, establishing a link between abnormal osteoclast function and bone loss in AIS. The results highlight that elevated CARD14 expression promotes osteoclastogenesis and bone resorption, contributing to reduced BMD in AIS. Targeting CARD14 and its associated signaling pathways may represent a novel therapeutic approach to address bone density loss in AIS patients, potentially improving their skeletal health and quality of life.</p>\",\"PeriodicalId\":185,\"journal\":{\"name\":\"Journal of Bone and Mineral Research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2025-09-15\",\"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/zjaf127\",\"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/zjaf127","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
CARD14-Mediated MYC Interaction Promotes Osteoclastogenesis and Bone Density Reduction in Adolescent Idiopathic Scoliosis.
Adolescent idiopathic scoliosis (AIS) is characterized by decreased bone mineral density (BMD), which is associated with an increased risk of skeletal fragility and poor long-term outcomes. This study explores the role of the CARD14 gene in osteoclast differentiation and its contribution to bone metabolism dysregulation in AIS patients. RNA sequencing of peripheral blood mononuclear cells (PBMCs) from AIS patients identified significantly elevated CARD14 expression compared to controls. Functional in vitro assays demonstrated enhanced osteoclastogenesis in PBMC-derived cells from AIS patients, as evidenced by an increase in TRAP-positive multinucleated cells and resorption pit formation. To further elucidate CARD14's role, adenoviral vectors were constructed to overexpress CARD14 in bone marrow-derived macrophages (BMMs) from C57/B6 mice, leading to markedly increased osteoclast differentiation and activity. Next, we utilized bone marrow-specific Card14 knockout mice to investigate the in vivo role of CARD14. These mice exhibited reduced osteoclast activity, improved trabecular bone microarchitecture, and increased BMD, as evidenced by micro-CT and histological analyses. Additionally, serum biomarkers of bone metabolism further corroborated these findings. Mechanistically, CARD14 was found to interact with MYC and regulate osteoclast differentiation through a MYC-dependent pathway, while simultaneously activating NF-κB and MAPK signaling, which are critical for osteoclastogenesis. AIS patients consistently showed lower BMD and higher osteoclast counts than age-matched controls, establishing a link between abnormal osteoclast function and bone loss in AIS. The results highlight that elevated CARD14 expression promotes osteoclastogenesis and bone resorption, contributing to reduced BMD in AIS. Targeting CARD14 and its associated signaling pathways may represent a novel therapeutic approach to address bone density loss in AIS patients, potentially improving their skeletal health and quality of life.
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.