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ATP6AP2, a regulator of LRP6/β-catenin protein trafficking, promotes Wnt/β-catenin signaling and bone formation in a cell type dependent manner ATP6AP2 是 LRP6/β-catenin 蛋白运输的调节因子,它以细胞类型依赖的方式促进 Wnt/β-catenin 信号传导和骨形成
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-29 DOI: 10.1038/s41413-024-00335-7
Lei Xiong, Hao-Han Guo, Jin-Xiu Pan, Xiao Ren, Daehoon Lee, Li Chen, Lin Mei, Wen-Cheng Xiong

Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types, including osteoblast (OB) differentiation and function. Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive. ATP6AP2, an accessory subunit of V-ATPase, plays important roles in multiple cell types/organs and multiple signaling pathways. However, little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone formation. Here we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone regions. Conditionally knocking out (CKO) ATP6AP2 in the OB-lineage cells (Atp6ap2Ocn-Cre) reduced trabecular, but not cortical, bone formation and bone mass. Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs, but not osteocytes. Additional in vitro and in vivo studies revealed impaired β-catenin signaling in ATP6AP2-KO BMSCs and OBs, but not osteocytes, under both basal and Wnt stimulated conditions, although LRP5 was decreased in ATP6AP2-KO osteocytes, but not BMSCs. Further cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression of β-catenin phosphorylation, but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane, thus preventing their degradation. Expression of active β-catenin diminished the OB differentiation deficit in ATP6AP2-KO BMSCs. Taken together, these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability, and thus regulating β-catenin levels, demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.

Wnt/β-catenin 信号对多种细胞类型的各种细胞过程至关重要,包括成骨细胞(OB)的分化和功能。Wnt/β-catenin信号在成骨细胞中究竟是如何调控的,至今仍是个谜。ATP6AP2是V-ATP酶的一个附属亚基,在多种细胞类型/器官和多种信号通路中发挥着重要作用。然而,ATP6AP2在OB中是否以及如何调节Wnt/β-catenin信号传导和骨形成却鲜为人知。在这里,我们提供了 OB 系细胞中的 ATP6AP2 选择性地在骨小梁区域促进 OB 介导的骨形成和骨稳态的证据。有条件地敲除(CKO)OB 系细胞中的 ATP6AP2(Atp6ap2Ocn-Cre)会减少骨小梁的骨形成和骨量,但不会减少皮质骨的形成和骨量。蛋白质组学和细胞生化研究显示,ATP6AP2-KO BMSCs 和 OBs 中的 LRP6 和 N-cadherin 减少了,但骨细胞没有减少。其他体外和体内研究显示,在基础和 Wnt 刺激条件下,ATP6AP2-KO BMSCs 和 OBs 中的β-catenin 信号转导受损,而成骨细胞没有受损,但 ATP6AP2-KO 成骨细胞中的 LRP5 减少,而 BMSCs 没有减少。进一步的细胞生物学研究发现,成骨细胞的 ATP6AP2 不是 Wnt3a 抑制β-catenin 磷酸化所必需的,但对于 LRP6/β-catenin 和 N-cadherin/β-catenin 蛋白复合物在细胞膜上的分布是必要的,从而阻止了它们的降解。表达活性β-catenin可减少ATP6AP2-KO BMSCs的OB分化缺陷。综上所述,这些结果支持了 ATP6AP2 是 LRP6 和 N-cadherin 蛋白运输和稳定性的关键调节因子的观点,从而调节了 β-catenin 的水平,证明了成骨细胞 ATP6AP2 在促进 Wnt/LRP6/β-catenin 信号传导和骨小梁形成方面具有尚未被认识的功能。
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引用次数: 0
Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3. 基质硬化通过下调 HDAC3 促进软骨细胞衰老和骨关节炎的发展。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-24 DOI: 10.1038/s41413-024-00333-9
Bowen Fu, Jianlin Shen, Xuenong Zou, Nian Sun, Ze Zhang, Zengping Liu, Canjun Zeng, Huan Liu, Wenhua Huang

Extracellular matrix (ECM) stiffening is a typical characteristic of cartilage aging, which is a quintessential feature of knee osteoarthritis (KOA). However, little is known about how ECM stiffening affects chondrocytes and other molecules downstream. This study mimicked the physiological and pathological stiffness of human cartilage using polydimethylsiloxane (PDMS) substrates. It demonstrated that epigenetic Parkin regulation by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiffness matrix affected chondrocyte physiology. We found that ECM stiffening accelerated cultured chondrocyte senescence in vitro, while the stiffness ECM downregulated HDAC3, prompting Parkin acetylation to activate excessive mitophagy and accelerating chondrocyte senescence and osteoarthritis (OA) in mice. Contrarily, intra-articular injection with an HDAC3-expressing adeno-associated virus restored the young phenotype of the aged chondrocytes stimulated by ECM stiffening and alleviated OA in mice. The findings indicated that changes in the mechanical ECM properties initiated pathogenic mechanotransduction signals, promoted the Parkin acetylation and hyperactivated mitophagy, and damaged chondrocyte health. These results may provide new insights into chondrocyte regulation by the mechanical properties of ECM, suggesting that the modification of the physical ECM properties may be a potential OA treatment strategy.

细胞外基质(ECM)硬化是软骨老化的典型特征,也是膝关节骨性关节炎(KOA)的典型特征。然而,人们对 ECM 硬化如何影响软骨细胞及其下游的其他分子知之甚少。本研究使用聚二甲基硅氧烷(PDMS)基底模拟了人体软骨的生理和病理硬度。研究表明,组蛋白去乙酰化酶 3(HDAC3)对表观遗传学 Parkin 的调控代表了一种新的机械敏感机制,通过这种机制,僵化基质会影响软骨细胞的生理机能。我们发现,ECM 变硬会加速体外培养的软骨细胞衰老,而僵化的 ECM 会下调 HDAC3,促使 Parkin 乙酰化,激活过度的有丝分裂,加速小鼠软骨细胞衰老和骨关节炎(OA)。相反,在小鼠关节内注射表达 HDAC3 的腺相关病毒,可使受 ECM 硬化刺激而衰老的软骨细胞恢复年轻表型,并缓解小鼠的 OA。研究结果表明,机械性 ECM 特性的变化启动了致病性机械传导信号,促进了 Parkin 乙酰化和有丝分裂亢进,损害了软骨细胞的健康。这些结果为了解软骨细胞受 ECM 机械特性的调控提供了新的视角,表明改变 ECM 的物理特性可能是一种潜在的 OA 治疗策略。
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引用次数: 0
Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis 肠道微生物代谢物靶向成纤维细胞样滑膜细胞中的 HDAC3-FOXK1-干扰素轴,从而改善类风湿性关节炎
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-23 DOI: 10.1038/s41413-024-00336-6
Hongzhen Chen, Xuekun Fu, Xiaohao Wu, Junyi Zhao, Fang Qiu, Zhenghong Wang, Zhuqian Wang, Xinxin Chen, Duoli Xie, Jie Huang, Junyu Fan, Xu Yang, Yi Song, Jie Li, Dongyi He, Guozhi Xiao, Aiping Lu, Chao Liang

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

类风湿性关节炎(RA)是一种自身免疫性疾病。早期的研究认为,肠道微生物群是由环境获得的,与类风湿关节炎的易感性有关。然而,越来越多的证据表明,遗传也会影响肠道微生物群。众所周知,一些近交系实验室小鼠对胶原诱导的关节炎(CIA)非常易感,而另一些则对CIA有抵抗力。在这里,我们展示了将对 CIA 有抵抗力的 C57BL/6J 小鼠的粪便微生物群移植到对 CIA 易感的 DBA/1J 小鼠体内,可赋予 DBA/1J 小鼠对 CIA 的抵抗力。与DBA/1J小鼠和RA患者相比,C57BL/6J小鼠和健康人富含脆弱拟杆菌。移植脆弱拟杆菌可预防DBA/1J小鼠的CIA。我们发现B. fragilis主要产生丙酸盐,而C57BL/6J小鼠和健康人体内丙酸盐含量较高。RA中的纤维母细胞样滑膜细胞(FLSs)被激活,发生肿瘤样转化。丙酸盐会破坏 HDAC3-FOXK1 的相互作用,从而增加 FOXK1 的乙酰化,导致 FOXK1 稳定性降低、干扰素信号传导受阻以及 RA-FLS 失活。我们用丙酸盐治疗 CIA 小鼠,结果表明丙酸盐可减轻 CIA。此外,丙酸盐与抗肿瘤坏死因子依那西普(etanercept)联合使用可协同缓解CIA。这些结果表明,B. fragilis或丙酸盐可以作为当前疗法的替代或补充方法。
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引用次数: 0
Author Correction: FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells. 作者更正:FAR591 通过调控 Fos 表达介导骨微血管内皮细胞凋亡,促进 SONFH 的发病和进展。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-20 DOI: 10.1038/s41413-024-00339-3
Fei Zhang, Lei Wei, Lei Wang, Tao Wang, Zhihong Xie, Hong Luo, Fanchao Li, Jian Zhang, Wentao Dong, Gang Liu, Qinglin Kang, Xuesong Zhu, Wuxun Peng
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引用次数: 0
RUFY4 deletion prevents pathological bone loss by blocking endo-lysosomal trafficking of osteoclasts. RUFY4 基因缺失会阻碍破骨细胞的内溶酶体运输,从而防止病理性骨质流失。
IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-05-15 DOI: 10.1038/s41413-024-00326-8
Minhee Kim, Jin Hee Park, Miyeon Go, Nawon Lee, Jeongin Seo, Hana Lee, Doyong Kim, Hyunil Ha, Taesoo Kim, Myeong Seon Jeong, Suree Kim, Taesoo Kim, Han Sung Kim, Dongmin Kang, Hyunbo Shim, Soo Young Lee

Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown. Here, we show with GeneChip analysis that RUN and FYVE domain-containing protein 4 (RUFY4) is strongly upregulated during osteoclastogenesis. Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo. Furthermore, deleting Rufy4 did not affect osteoclast differentiation, but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes, their trafficking to the membrane, and their secretion of cathepsin K into the extracellular space. Mechanistically, RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes. Consequently, Rufy4-deficient mice were highly protected from lipopolysaccharide- and ovariectomy-induced bone loss. Thus, RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.

成熟的破骨细胞通过褶皱边界从分泌溶酶体中排出活性蛋白酶,从而降解骨基质。然而,破骨细胞溶酶体转运和分泌的分子机制在很大程度上仍不为人知。在这里,我们通过基因芯片分析表明,在破骨细胞生成过程中,含 RUN 和 FYVE 结构域的蛋白 4(RUFY4)被强烈上调。缺乏 Rufy4 的小鼠表现出高小梁骨量表型,体内破骨细胞功能异常。此外,删除 Rufy4 不会影响破骨细胞的分化,但会抑制破骨细胞的骨吸收活性,这是由于次级溶酶体的酸性成熟、向膜的转运以及向细胞外空间分泌 cathepsin K 的过程受到了破坏。从机理上讲,RUFY4 作为晚期内体上的 Rab7 与初级溶酶体上的 LAMP2 之间的适配蛋白,可促进晚期内体与溶酶体的融合。因此,Rufy4缺陷小鼠对脂多糖和卵巢切除术诱导的骨质流失具有高度保护作用。因此,RUFY4通过介导内溶酶体转运而成为破骨细胞活性的新调节因子,并有可能成为骨质疏松症等骨丢失疾病的特异性治疗靶点。
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引用次数: 0
Prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections 应用组织工程技术治疗骨感染的前景与挑战
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-14 DOI: 10.1038/s41413-024-00332-w
Leilei Qin, Shuhao Yang, Chen Zhao, Jianye Yang, Feilong Li, Zhenghao Xu, Yaji Yang, Haotian Zhou, Kainan Li, Chengdong Xiong, Wei Huang, Ning Hu, Xulin Hu

Osteomyelitis is a devastating disease caused by microbial infection in deep bone tissue. Its high recurrence rate and impaired restoration of bone deficiencies are major challenges in treatment. Microbes have evolved numerous mechanisms to effectively evade host intrinsic and adaptive immune attacks to persistently localize in the host, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants (SCVs). Moreover, microbial-mediated dysregulation of the bone immune microenvironment impedes the bone regeneration process, leading to impaired bone defect repair. Despite advances in surgical strategies and drug applications for the treatment of bone infections within the last decade, challenges remain in clinical management. The development and application of tissue engineering materials have provided new strategies for the treatment of bone infections, but a comprehensive review of their research progress is lacking. This review discusses the critical pathogenic mechanisms of microbes in the skeletal system and their immunomodulatory effects on bone regeneration, and highlights the prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections. It will inform the development and translation of antimicrobial and bone repair tissue engineering materials for the management of bone infections.

骨髓炎是一种由深层骨组织微生物感染引起的破坏性疾病。它的高复发率和骨缺损恢复受损是治疗中的主要挑战。微生物已进化出多种机制,如耐药细菌、生物膜、持久细胞、细胞内细菌和小菌落变异体(SCVs)等,可有效躲避宿主内在和适应性免疫攻击,在宿主体内持久存在。此外,微生物介导的骨免疫微环境失调会阻碍骨再生过程,导致骨缺损修复受损。尽管近十年来治疗骨感染的手术策略和药物应用取得了进展,但临床管理仍面临挑战。组织工程材料的开发和应用为治疗骨感染提供了新的策略,但目前还缺乏对其研究进展的全面回顾。本综述探讨了微生物在骨骼系统中的关键致病机制及其对骨再生的免疫调节作用,并强调了组织工程技术在骨感染治疗中的应用前景和挑战。它将为开发和转化用于治疗骨感染的抗菌和骨修复组织工程材料提供参考。
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引用次数: 0
Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration 对人体肌腱粘附的多组学分析表明,ACKR1调控的巨噬细胞迁移参与了再生过程
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-07 DOI: 10.1038/s41413-024-00324-w
Xinshu Zhang, Yao Xiao, Bo Hu, Yanhao Li, Shaoyang Zhang, Jian Tian, Shuo Wang, Zaijin Tao, Xinqi Zeng, Ning-Ning Liu, Baojie Li, Shen Liu

Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1−/− mice (Ackr1−/− chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

肌腱粘连是肌腱损伤后常见的并发症,在没有有效抗纤维化疗法的情况下,会形成累积性纤维化组织,导致严重残疾。巨噬细胞被广泛认为是肌腱周围粘连形成过程中的纤维化诱因。然而,不同的巨噬细胞集群具有不同的功能,并受到多重调控,而这两点目前都还是未知数。在我们目前的研究中,我们对人类和小鼠肌腱损伤后不同阶段的肌腱粘连组织进行了多组学分析,包括单细胞 RNA 测序和蛋白质组学。我们对超过 74000 个人类单细胞的转录组进行了分析。结果发现,SPP1+巨噬细胞、RGCC+内皮细胞、ACKR1+内皮细胞和ADAM12+成纤维细胞参与了肌腱粘连的形成。有趣的是,尽管肌腱粘连中存在特定的纤维化集群,但利用人体细胞进行的体外实验发现,FOLR2+巨噬细胞是抗纤维化集群。此外,通过将Lysm-Cre;R26RtdTomato小鼠的骨髓移植到经致命照射的Ackr1-/-小鼠(Ackr1-/-嵌合体;缺乏ACKR1)和对照小鼠(WT嵌合体)体内,验证了ACKR1能调节FOLR2+巨噬细胞在损伤的腱周部位的迁移。与 WT 嵌合体相比,我们还观察到 FOLR2+ 巨噬细胞的减少,这表明 ACKR1 特别参与了 FOLR2+ 巨噬细胞的迁移。综上所述,我们的研究不仅通过多组学分析描述了肌腱粘附的纤维化微环境图谱,还发现了一个新的巨噬细胞抗纤维化集群及其起源。这些结果为人类肌腱粘连提供了潜在的治疗靶点。
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引用次数: 0
Pannexins in the musculoskeletal system: new targets for development and disease progression 肌肉骨骼系统中的泛内联蛋白:发展和疾病进展的新目标
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-06 DOI: 10.1038/s41413-024-00334-8
Yan Luo, Shengyuan Zheng, Wenfeng Xiao, Hang Zhang, Yusheng Li

During cell differentiation, growth, and development, cells can respond to extracellular stimuli through communication channels. Pannexin (Panx) family and connexin (Cx) family are two important types of channel-forming proteins. Panx family contains three members (Panx1-3) and is expressed widely in bone, cartilage and muscle. Although there is no sequence homology between Panx family and Cx family, they exhibit similar configurations and functions. Similar to Cxs, the key roles of Panxs in the maintenance of physiological functions of the musculoskeletal system and disease progression were gradually revealed later. Here, we seek to elucidate the structure of Panxs and their roles in regulating processes such as osteogenesis, chondrogenesis, and muscle growth. We also focus on the comparison between Cx and Panx. As a new key target, Panxs expression imbalance and dysfunction in muscle and the therapeutic potentials of Panxs in joint diseases are also discussed.

在细胞分化、生长和发育过程中,细胞可通过通讯通道对细胞外的刺激做出反应。Pannexin(Panx)家族和 connexin(Cx)家族是两种重要的通道形成蛋白。Panx 家族包含三个成员(Panx1-3),在骨骼、软骨和肌肉中广泛表达。虽然 Panx 家族与 Cx 家族之间没有序列同源性,但它们具有相似的结构和功能。与 Cxs 类似,Panxs 在维持肌肉骨骼系统生理功能和疾病进展中的关键作用也在后来逐渐被揭示。在此,我们试图阐明 Panxs 的结构及其在调控骨生成、软骨生成和肌肉生长等过程中的作用。我们还关注了 Cx 和 Panx 之间的比较。作为一个新的关键靶点,我们还讨论了 Panxs 在肌肉中的表达失衡和功能障碍,以及 Panxs 在关节疾病中的治疗潜力。
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引用次数: 0
Author Correction: Insights and implications of sexual dimorphism in osteoporosis 作者更正:骨质疏松症中性双态性的见解和影响
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-15 DOI: 10.1038/s41413-024-00329-5
Yuan-Yuan Zhang, Na Xie, Xiao-Dong Sun, Edouard C. Nice, Y. Liou, Canhua Huang, Huili Zhu, Zhisen Shen
{"title":"Author Correction: Insights and implications of sexual dimorphism in osteoporosis","authors":"Yuan-Yuan Zhang, Na Xie, Xiao-Dong Sun, Edouard C. Nice, Y. Liou, Canhua Huang, Huili Zhu, Zhisen Shen","doi":"10.1038/s41413-024-00329-5","DOIUrl":"https://doi.org/10.1038/s41413-024-00329-5","url":null,"abstract":"","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140702614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sorafenib inhibits ossification of the posterior longitudinal ligament by blocking LOXL2-mediated vascularization 索拉非尼通过阻断 LOXL2 介导的血管生成抑制后纵韧带骨化
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-10 DOI: 10.1038/s41413-024-00327-7
Longqing Wang, Wenhao Jiang, Siyuan Zhao, Dong Xie, Qing Chen, Qi Zhao, Hao Wu, Jian Luo, Lili Yang

Ossification of the Posterior Longitudinal Ligament (OPLL) is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone, resulting in limited spinal mobility and nerve compression. Employing both bulk and single-cell RNA sequencing, we elucidate the molecular characteristics, cellular components, and their evolution during the OPLL process at a single-cell resolution, and validate these findings in clinical samples. This study also uncovers the capability of ligament stem cells to exhibit endothelial cell-like phenotypes in vitro and in vivo. Notably, our study identifies LOXL2 as a key regulator in this process. Through gain-and loss-of-function studies, we elucidate the role of LOXL2 in the endothelial-like differentiation of ligament cells. It acts via the HIF1A pathway, promoting the secretion of downstream VEGFA and PDGF-BB. This function is not related to the enzymatic activity of LOXL2. Furthermore, we identify sorafenib, a broad-spectrum tyrosine kinase inhibitor, as an effective suppressor of LOXL2-mediated vascular morphogenesis. By disrupting the coupling between vascularization and osteogenesis, sorafenib demonstrates significant inhibition of OPLL progression in both BMP-induced and enpp1 deficiency-induced animal models while having no discernible effect on normal bone mass. These findings underscore the potential of sorafenib as a therapeutic intervention for OPLL.

后纵韧带骨化(OPLL)是一种退行性骨质疏松疾病,其特点是柔软而富有弹性的椎韧带转变为骨质,导致脊柱活动受限和神经受压。我们采用大量和单细胞 RNA 测序技术,以单细胞分辨率阐明了 OPLL 过程中的分子特征、细胞成分及其演变,并在临床样本中验证了这些发现。这项研究还揭示了韧带干细胞在体外和体内表现出内皮细胞样表型的能力。值得注意的是,我们的研究发现LOXL2是这一过程中的关键调节因子。通过功能增益和功能缺失研究,我们阐明了LOXL2在韧带细胞内皮样分化中的作用。它通过 HIF1A 途径发挥作用,促进下游 VEGFA 和 PDGF-BB 的分泌。这一功能与 LOXL2 的酶活性无关。此外,我们还发现索拉非尼(一种广谱酪氨酸激酶抑制剂)能有效抑制 LOXL2 介导的血管形态发生。通过破坏血管形成和骨生成之间的耦合,索拉非尼在BMP诱导和enpp1缺乏诱导的动物模型中都能显著抑制OPLL的进展,同时对正常骨量没有明显影响。这些发现强调了索拉非尼作为OPLL治疗干预措施的潜力。
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引用次数: 0
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Bone Research
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