Luo Hao, Lin Sijian, Xiong Jiachao, Tan Wen, Lv Hao, Liu Zhiming, Wu Qin, Zhong Junlong, Cao Kai
Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
The Key Laboratory of Spine and Spinal Cord Disease of Jiangxi Province, Nanchang 330006, China.
J Bone Miner Res. 2025 Sep 15. doi: 10.1093/jbmr/zjaf127.
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.
青少年特发性脊柱侧凸（AIS）的特征是骨矿物质密度（BMD）降低，这与骨骼脆性增加和长期预后不良有关。本研究探讨了CARD14基因在破骨细胞分化中的作用及其对AIS患者骨代谢失调的影响。与对照组相比，对AIS患者外周血单核细胞（PBMC）进行RNA测序发现CARD14表达显著升高。体外功能分析表明，AIS患者PBMC来源的细胞中破骨细胞生成增强，TRAP阳性多核细胞增加和吸收陷窝形成可证明这一点。为了进一步阐明CARD14的作用，构建了腺病毒载体以在C57/B6小鼠的骨髓来源巨噬细胞（BMM）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基因敲除小鼠来研究CARD14在体内的作用。显微CT和组织学分析表明，这些小鼠的破骨细胞活性降低，小梁骨微结构改善，骨矿物质密度增加。此外，骨代谢的血清生物标志物进一步证实了这些发现。从机制上讲，发现CARD14与MYC相互作用并通过MYC依赖性途径调节破骨细胞分化，同时激活对破骨细胞生成至关重要的NF-κB和MAPK信号通路。AIS患者始终显示出比年龄匹配的对照组更低的骨矿物质密度和更高的破骨细胞计数，这在AIS患者的破骨细胞功能异常与骨质流失之间建立了联系。结果表明，CARD14表达升高促进破骨细胞生成和骨吸收，导致AIS患者骨矿物质密度降低。靶向CARD14及其相关信号通路可能代表一种新的治疗方法，以解决AIS患者的骨密度损失问题，有可能改善他们的骨骼健康和生活质量。
