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。

IF 5.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Hao Luo, Sijian Lin, Jiachao Xiong, Wen Tan, Hao Lv, Zhiming Liu, Qin Wu, Junlong Zhong, Kai Cao
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引用次数: 0

摘要

青少年特发性脊柱侧凸(AIS)的特点是骨密度(BMD)降低,这与骨骼脆性风险增加和长期预后不良有关。本研究探讨了CARD14基因在AIS患者破骨细胞分化中的作用及其在骨代谢失调中的作用。AIS患者外周血单个核细胞(PBMCs)的RNA测序发现,与对照组相比,CARD14的表达显著升高。体外功能实验表明,AIS患者的pbmc来源细胞的破骨细胞生成增强,trap阳性的多核细胞和再吸收坑形成增加。为了进一步阐明CARD14的作用,我们构建腺病毒载体,在C57/B6小鼠骨髓源性巨噬细胞(BMMs)中过表达CARD14,导致破骨细胞分化和活性显著增加。接下来,我们利用骨髓特异性Card14敲除小鼠来研究Card14在体内的作用。显微ct和组织学分析证明,这些小鼠表现出破骨细胞活性降低,骨小梁微结构改善,骨密度增加。此外,骨代谢的血清生物标志物进一步证实了这些发现。在机制上,CARD14被发现与MYC相互作用,通过MYC依赖性途径调节破骨细胞分化,同时激活NF-κB和MAPK信号,这对破骨细胞的发生至关重要。与年龄匹配的对照组相比,AIS患者一贯表现出较低的骨密度和较高的破骨细胞计数,这在AIS患者中建立了破骨细胞功能异常与骨质流失之间的联系。结果表明,CARD14表达升高可促进破骨细胞生成和骨吸收,从而降低AIS患者的骨密度。靶向CARD14及其相关信号通路可能是解决AIS患者骨密度损失的一种新的治疗方法,有可能改善其骨骼健康和生活质量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
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.
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