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Retraction Note: Circular RNA circStag1 promotes bone regeneration by interacting with HuR. 撤稿说明:环状 RNA circStag1 通过与 HuR 相互作用促进骨再生。
IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-06-24 DOI: 10.1038/s41413-024-00348-2
Gaoyang Chen, Canling Long, Shang Wang, Zhenmin Wang, Xin Chen, Wanze Tang, Xiaoqin He, Zhiteng Bao, Baoyu Tan, Jin Zhao, Yongheng Xie, Zhizhong Li, Dazhi Yang, Guozhi Xiao, Songlin Peng
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引用次数: 0
FGF signaling modulates mechanotransduction/WNT signaling in progenitors during tooth root development. 牙根发育过程中,FGF 信号调节祖细胞中的机械传导/WNT 信号。
IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-06-24 DOI: 10.1038/s41413-024-00345-5
Fei Pei, Tingwei Guo, Mingyi Zhang, Li Ma, Junjun Jing, Jifan Feng, Thach-Vu Ho, Quan Wen, Yang Chai

Stem/progenitor cells differentiate into different cell lineages during organ development and morphogenesis. Signaling pathway networks and mechanotransduction are important factors to guide the lineage commitment of stem/progenitor cells during craniofacial tissue morphogenesis. Here, we used tooth root development as a model to explore the roles of FGF signaling and mechanotransduction as well as their interaction in regulating the progenitor cell fate decision. We show that Fgfr1 is expressed in the mesenchymal progenitor cells and their progeny during tooth root development. Loss of Fgfr1 in Gli1+ progenitors leads to hyperproliferation and differentiation, which causes narrowed periodontal ligament (PDL) space with abnormal cementum/bone formation leading to ankylosis. We further show that aberrant activation of WNT signaling and mechanosensitive channel Piezo2 occurs after loss of FGF signaling in Gli1-CreER;Fgfr1fl/fl mice. Overexpression of Piezo2 leads to increased osteoblastic differentiation and decreased Piezo2 leads to downregulation of WNT signaling. Mechanistically, an FGF/PIEZO2/WNT signaling cascade plays a crucial role in modulating the fate of progenitors during root morphogenesis. Downregulation of WNT signaling rescues tooth ankylosis in Fgfr1 mutant mice. Collectively, our findings uncover the mechanism by which FGF signaling regulates the fate decisions of stem/progenitor cells, and the interactions among signaling pathways and mechanotransduction during tooth root development, providing insights for future tooth root regeneration.

干细胞/祖细胞在器官发育和形态发生过程中会分化成不同的细胞系。信号通路网络和机械传导是颅面组织形态发生过程中引导干细胞/祖细胞系承的重要因素。在这里,我们以牙根的发育为模型,探讨了FGF信号传导和机械传导在调控祖细胞命运决定中的作用及其相互作用。我们发现,在牙根发育过程中,Fgfr1在间充质祖细胞及其后代中表达。Gli1+ 祖细胞中 Fgfr1 的缺失会导致过度增殖和分化,从而造成牙周韧带(PDL)空间狭窄,骨水泥/骨形成异常,导致强直。我们进一步发现,Gli1-CreER;Fgfr1fl/fl 小鼠失去 FGF 信号后,WNT 信号和机械敏感通道 Piezo2 会发生异常激活。过表达 Piezo2 会导致成骨细胞分化增加,而减少 Piezo2 会导致 WNT 信号下调。从机制上讲,FGF/PIEZO2/WNT 信号级联在根形态发生过程中对祖细胞的命运起着至关重要的调节作用。下调 WNT 信号可挽救 Fgfr1 突变小鼠的牙齿强直。总之,我们的研究结果揭示了牙根发育过程中FGF信号调节干细胞/祖细胞命运决定的机制,以及信号通路和机械传导之间的相互作用,为未来的牙根再生提供了启示。
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引用次数: 0
Involvement of Siglec-15 in regulating RAP1/RAC signaling in cytoskeletal remodeling in osteoclasts mediated by macrophage colony-stimulating factor Siglec-15 参与调节巨噬细胞集落刺激因子介导的破骨细胞细胞骨架重塑过程中的 RAP1/RAC 信号传导
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-06-07 DOI: 10.1038/s41413-024-00340-w
Hideyuki Kobayashi, M. Alaa Terkawi, Masahiro Ota, Tomoka Hasegawa, Tomomaya Yamamoto, Tomohiro Shimizu, Dai Sato, Ryo Fujita, Toshifumi Murakami, Norio Amizuka, Norimasa Iwasaki, Masahiko Takahata

DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals essential for osteoclastogenesis. Although several DAP12-associated receptors (DARs) have been identified in osteoclasts, including triggering receptor expressed on myeloid cells 2 (TREM-2), C-type lectin member 5 A (CLEC5A), and sialic acid-binding Ig-like lectin (Siglec)-15, their precise role in the development of osteoclasts and bone remodeling remain poorly understood. In this study, mice deficient in Trem-2, Clec5a, Siglec-15 were generated. In addition, mice double deficient in these DAR genes and FcεRI gamma chain (FcR)γ, an alternative ITAM adaptor to DAP12, were generated. Bone mass analysis was conducted on all mice. Notably, Siglec-15 deficient mice and Siglec-15/FcRγ double deficient mice exhibited mild and severe osteopetrosis respectively. In contrast, other DAR deficient mice showed normal bone phenotype. Likewise, osteoclasts from Siglec-15 deficient mice failed to form an actin ring, suggesting that Siglec-15 promotes bone resorption principally by modulating the cytoskeletal organization of osteoclasts. Furthermore, biochemical analysis revealed that Sigelc-15 activates macrophage colony-stimulating factor (M-CSF)-induced Ras-associated protein-1 (RAP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway through formation of a complex with p130CAS and CrkII, leading to cytoskeletal remodeling of osteoclasts. Our data provide genetic and biochemical evidence that Siglec-15 facilitates M-CSF-induced cytoskeletal remodeling of the osteoclasts.

DNAX 相关蛋白 12 kD 大小(DAP12)是一种优势免疫受体酪氨酸基激活基序(ITAM)信号适配体,可激活破骨细胞生成所必需的成本刺激信号。虽然已在破骨细胞中发现了几种 DAP12 相关受体(DAR),包括髓系细胞上表达的触发受体 2(TREM-2)、C 型凝集素成员 5 A(CLEC5A)和唾液酸结合 Ig 样凝集素(Siglec)-15,但它们在破骨细胞的发育和骨重塑中的确切作用仍鲜为人知。在这项研究中,我们培育出了缺乏 Trem-2、Clec5a 和 Siglec-15 的小鼠。此外,还产生了这些 DAR 基因和 FcεRI γ 链(FcR)γ(DAP12 的另一种 ITAM 适配体)双重缺失的小鼠。对所有小鼠进行了骨量分析。值得注意的是,Siglec-15缺陷小鼠和Siglec-15/FcRγ双缺陷小鼠分别表现出轻度和重度骨质疏松。相比之下,其他 DAR 缺陷小鼠则表现出正常的骨表型。同样,Siglec-15缺陷小鼠的破骨细胞也不能形成肌动蛋白环,这表明Siglec-15主要通过调节破骨细胞的细胞骨架组织来促进骨吸收。此外,生化分析表明,Sigelc-15 通过与 p130CAS 和 CrkII 形成复合物,激活巨噬细胞集落刺激因子(M-CSF)诱导的 Ras 相关蛋白-1(RAP1)/Ras 相关 C3 肉毒毒素底物 1(Rac1)通路,从而导致破骨细胞的细胞骨架重塑。我们的数据提供了遗传和生化证据,证明 Siglec-15 可促进 M-CSF 诱导的破骨细胞细胞骨架重塑。
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引用次数: 0
Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling 腰椎失稳通过 Hippo-CCL3 信号招募破骨细胞,重塑软骨终板,诱发椎间盘退变
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-05-30 DOI: 10.1038/s41413-024-00331-x
Hanwen Li, Yingchuang Tang, Zixiang Liu, Kangwu Chen, Kai Zhang, Sihan Hu, Chun Pan, Huilin Yang, Bin Li, Hao Chen

Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration.

退化的椎间盘终板具有干酪样形态和感觉神经支配,可导致腰背痛,进而诱发老年人群的椎间盘退变。在本研究中,我们报告了腰椎失稳诱导的软骨终板重塑是导致这种病理变化的原因。对异常应力下软骨终板软骨细胞的转录组测序发现,Hippo 信号是这一过程的关键。激活Hippo信号或敲除软骨终板中的关键基因Yap1可切断腰椎不稳(LSI)手术后的干酪样形态改变和椎间盘退变,而阻断Hippo信号则可逆转这一过程。同时,转录组测序数据还显示,在异常机械应力作用下,软骨终板软骨细胞中破骨细胞分化相关基因组的表达被上调,而Hippo信号被激活后,破骨细胞分化相关基因组的表达也被上调。在已发现的破骨细胞分化基因组中,CCL3被发现在异常应力下从软骨细胞中大量释放,其功能是招募和促进破骨细胞的形成,从而实现软骨终板的重塑。过度表达Yap1可通过阻断其启动子抑制CCL3的转录,从而使软骨终板从重塑形态逆转为干酪样形态。最后,通过在局部注射AAV5包裹的Yap1过度表达质粒,成功地挽救了LSI诱导的软骨终板重塑。这些研究结果表明,Hippo 信号诱导的软骨终板破骨细胞基因组激活是治疗不稳定诱发的腰痛和腰椎退化的潜在新靶点。
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引用次数: 0
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 CELL & TISSUE ENGINEERING 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。
{"title":"ATP6AP2, a regulator of LRP6/β-catenin protein trafficking, promotes Wnt/β-catenin signaling and bone formation in a cell type dependent manner","authors":"Lei Xiong, Hao-Han Guo, Jin-Xiu Pan, Xiao Ren, Daehoon Lee, Li Chen, Lin Mei, Wen-Cheng Xiong","doi":"10.1038/s41413-024-00335-7","DOIUrl":"https://doi.org/10.1038/s41413-024-00335-7","url":null,"abstract":"<p>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 (<i>Atp6ap2</i><sup><i>Ocn-Cre</i></sup>) reduced trabecular, but not cortical, bone formation and bone mass. Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in <i>ATP6AP2-KO</i> BMSCs and OBs, but not osteocytes. Additional in vitro and in vivo studies revealed impaired β-catenin signaling in <i>ATP6AP2-KO</i> BMSCs and OBs, but not osteocytes, under both basal and Wnt stimulated conditions, although LRP5 was decreased in <i>ATP6AP2-KO</i> 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 <i>ATP6AP2-KO</i> 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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"29 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165389","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
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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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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Bone Research
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