{"title":"Inhibition of inflammatory osteoclasts accelerates callus remodeling in osteoporotic fractures by enhancing CGRP+TrkA+ signaling","authors":"Yuexia Shu, Zhenyu Tan, Zhen Pan, Yujie Chen, Jielin Wang, Jieming He, Jia Wang, Yuan Wang","doi":"10.1038/s41418-024-01368-5","DOIUrl":"https://doi.org/10.1038/s41418-024-01368-5","url":null,"abstract":"<p>Impaired callus remodeling significantly contributes to the delayed healing of osteoporotic fractures; however, the underlying mechanisms remain unclear. Sensory neuronal signaling plays a crucial role in bone repair. In this study, we aimed to investigate the pathological mechanisms hindering bone remodeling in osteoporotic fractures, particularly focusing on the role of sensory neuronal signaling. We demonstrate that in ovariectomized (OVX) mice, the loss of CGRP<sup>+</sup>TrkA<sup>+</sup> sensory neuronal signaling during callus remodeling correlates with increased Cx3cr1<sup>+</sup>iOCs expression within the bone callus. Conditional knockout of Cx3cr1<sup>+</sup>iOCs restored CGRP<sup>+</sup>TrkA<sup>+</sup> sensory neuronal, enabling normal callus remodeling progression. Mechanistically, we further demonstrate that Cx3cr1<sup>+</sup>iOCs secrete Sema3A in the osteoporotic fracture repair microenvironment, inhibiting CGRP<sup>+</sup>TrkA<sup>+</sup> sensory neurons’ axonal regeneration and suppressing nerve–bone signaling exchange, thus hindering bone remodeling. Lastly, in human samples, we observed an association between the loss of CGRP<sup>+</sup>TrkA<sup>+</sup> sensory neuronal signaling and increased expression of Cx3cr1<sup>+</sup>iOCs. In conclusion, enhancing CGRP<sup>+</sup>TrkA<sup>+</sup> sensory nerve signaling by inhibiting Cx3cr1<sup>+</sup>iOCs activity presents a potential strategy for treating delayed healing in osteoporotic fractures.</p><figure><p>Inhibition of inflammatory osteoclasts enhances CGRP<sup>+</sup>TrkA<sup>+</sup> signaling and accelerates callus remodeling in osteoporotic fractures.</p></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"66 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Publisher Correction: Cell death as an architect of adult skin stem cell niches","authors":"Kim Lecomte, Annagiada Toniolo, Esther Hoste","doi":"10.1038/s41418-024-01362-x","DOIUrl":"10.1038/s41418-024-01362-x","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 10","pages":"1390-1390"},"PeriodicalIF":13.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01362-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yu-Guang Chen, Eva Rieser, Amandeep Bhamra, Silvia Surinova, Peter Kreuzaler, Meng-Hsing Ho, Wen-Chiuan Tsai, Nieves Peltzer, Diego de Miguel, Henning Walczak
{"title":"LUBAC enables tumor-promoting LTβ receptor signaling by activating canonical NF-κB","authors":"Yu-Guang Chen, Eva Rieser, Amandeep Bhamra, Silvia Surinova, Peter Kreuzaler, Meng-Hsing Ho, Wen-Chiuan Tsai, Nieves Peltzer, Diego de Miguel, Henning Walczak","doi":"10.1038/s41418-024-01355-w","DOIUrl":"10.1038/s41418-024-01355-w","url":null,"abstract":"Lymphotoxin β receptor (LTβR), a member of the TNF receptor superfamily (TNFR-SF), is essential for development and maturation of lymphoid organs. In addition, LTβR activation promotes carcinogenesis by inducing a proinflammatory secretome. Yet, we currently lack a detailed understanding of LTβR signaling. In this study we discovered the linear ubiquitin chain assembly complex (LUBAC) as a previously unrecognized and functionally crucial component of the native LTβR signaling complex (LTβR-SC). Mechanistically, LUBAC-generated linear ubiquitin chains enable recruitment of NEMO, OPTN and A20 to the LTβR-SC, where they act coordinately to regulate the balance between canonical and non-canonical NF-κB pathways. Thus, different from death receptor signaling, where LUBAC prevents inflammation through inhibition of cell death, in LTβR signaling LUBAC is required for inflammatory signaling by enabling canonical and interfering with non-canonical NF-κB activation. This results in a LUBAC-dependent LTβR-driven inflammatory, protumorigenic secretome. Intriguingly, in liver cancer patients with high LTβR expression, high expression of LUBAC correlates with poor prognosis, providing clinical relevance for LUBAC-mediated inflammatory LTβR signaling.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 10","pages":"1267-1284"},"PeriodicalIF":13.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01355-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiyeon Lee, Fumiyuki Sasaki, Eri Koike, Minjeong Cho, Yeongun Lee, So Hee Dho, Jina Lee, Eunji Lee, Eri Toyohara, Mika Sunakawa, Mariko Ishibashi, Huynh Hiep Hung, Saki Nishioka, Ritsuko Komine, Chiaki Okura, Masumi Shimizu, Masahito Ikawa, Akihiko Yoshimura, Rimpei Morita, Lark Kyun Kim
{"title":"Gelsolin alleviates rheumatoid arthritis by negatively regulating NLRP3 inflammasome activation","authors":"Jiyeon Lee, Fumiyuki Sasaki, Eri Koike, Minjeong Cho, Yeongun Lee, So Hee Dho, Jina Lee, Eunji Lee, Eri Toyohara, Mika Sunakawa, Mariko Ishibashi, Huynh Hiep Hung, Saki Nishioka, Ritsuko Komine, Chiaki Okura, Masumi Shimizu, Masahito Ikawa, Akihiko Yoshimura, Rimpei Morita, Lark Kyun Kim","doi":"10.1038/s41418-024-01367-6","DOIUrl":"https://doi.org/10.1038/s41418-024-01367-6","url":null,"abstract":"<p>Despite numerous biomarkers being proposed for rheumatoid arthritis (RA), a gap remains in our understanding of their mechanisms of action. In this study, we discovered a novel role for gelsolin (GSN), an actin-binding protein whose levels are notably reduced in the plasma of RA patients. We elucidated that GSN is a key regulator of NLRP3 inflammasome activation in macrophages, providing a plausible explanation for the decreased secretion of GSN in RA patients. We found that GSN interacts with NLRP3 in LPS-primed macrophages, hence modulating the formation of the NLRP3 inflammasome complex. Reducing GSN expression significantly enhanced NLRP3 inflammasome activation. GSN impeded NLRP3 translocation to the mitochondria; it contributed to the maintenance of intracellular calcium equilibrium and mitochondrial stability. This maintenance is crucial for controlling the inflammatory response associated with RA. Furthermore, the exacerbation of arthritic symptoms in GSN-deficient mice indicates the potential of GSN as both a diagnostic biomarker and a therapeutic target. Moreover, not limited to RA models, GSN has demonstrated a protective function in diverse disease models associated with the NLRP3 inflammasome. Myeloid cell-specific GSN-knockout mice exhibited aggravated inflammatory responses in models of MSU-induced peritonitis, folic acid-induced acute tubular necrosis, and LPS-induced sepsis. These findings suggest novel therapeutic approaches that modulate GSN activity, offering promise for more effective management of RA and a broader spectrum of inflammatory conditions.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"28 22 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jia Xiu Zhang, Pei Pei Chen, Xue Qi Li, Liang Li, Qin Yi Wu, Gui Hua Wang, Xiong Zhong Ruan, Kun Ling Ma
{"title":"Deficiency of thiosulfate sulfurtransferase mediates the dysfunction of renal tubular mitochondrial fatty acid oxidation in diabetic kidney disease.","authors":"Jia Xiu Zhang, Pei Pei Chen, Xue Qi Li, Liang Li, Qin Yi Wu, Gui Hua Wang, Xiong Zhong Ruan, Kun Ling Ma","doi":"10.1038/s41418-024-01365-8","DOIUrl":"https://doi.org/10.1038/s41418-024-01365-8","url":null,"abstract":"<p><p>One of the main characteristics of diabetic kidney disease (DKD) is abnormal renal tubular fatty acid metabolism, especially defective fatty acid oxidation (FAO), accelerating tubular injury and tubulointerstitial fibrosis. Thiosulfate sulfurtransferase (TST), a mitochondrial enzyme essential for sulfur transfer, is reduced in metabolic diseases like diabetes and obesity. However, the potential role of TST in regulating fatty acid metabolic abnormalities in DKD remains unclear. Here, our data revealed decreased TST expression in the renal cortex of DKD patients. TST deficiency exacerbated tubular impairment in both diabetic and renal fibrosis mouse models, while sodium thiosulfate treatment or TST overexpression mitigated renal tubular injury with high-glucose exposure. TST downregulation mediated the decrease in S-sulfhydration of very long-chain specific acyl-CoA dehydrogenase, resulting in mitochondrial FAO dysfunction. This sequence of events exacerbates the progression of tubulointerstitial injury in DKD. Together, our findings demonstrate TST as a regulator of renal tubular injury in DKD.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yunying Yang, Sichun Chen, Li Zhang, Guoxin Zhang, Yan Liu, Yiming Li, Li Zou, Lanxia Meng, Ye Tian, Lijun Dai, Min Xiong, Lina Pan, Jing Xiong, Liam Chen, Hua Hou, Zhui Yu, Zhentao Zhang
{"title":"The PM20D1-NADA pathway protects against Parkinson’s disease","authors":"Yunying Yang, Sichun Chen, Li Zhang, Guoxin Zhang, Yan Liu, Yiming Li, Li Zou, Lanxia Meng, Ye Tian, Lijun Dai, Min Xiong, Lina Pan, Jing Xiong, Liam Chen, Hua Hou, Zhui Yu, Zhentao Zhang","doi":"10.1038/s41418-024-01356-9","DOIUrl":"10.1038/s41418-024-01356-9","url":null,"abstract":"Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD. Single nucleotide polymorphisms regulating PM20D1 expression are associated with changed risk of PD. Dopamine (DA) metabolism and DA metabolites have been reported to regulate α-Syn pathology. Here we report that PM20D1 catalyzes the conversion of DA to N-arachidonoyl dopamine (NADA), which interacts with α-Syn and inhibits its aggregation. Simultaneously, NADA competes with α-Syn fibrils to regulate TRPV4-mediated calcium influx and downstream phosphatases, thus alleviating α-Syn phosphorylation. The expression of PM20D1 decreases during aging. Overexpression of PM20D1 or the administration of NADA in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. These observations support the protective effect of the PM20D1-NADA pathway against the progression of α-Syn pathology in PD.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1545-1560"},"PeriodicalIF":13.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhenya Tan, Ke Pan, Minqiong Sun, Xianzhu Pan, Zhi Yang, Zhiling Chang, Xue Yang, Jicheng Zhu, Li Zhan, Yakun Liu, Xiaofei Li, Keqiong Lin, Lin Chen, Hui Mo, Wei Luo, Chen Kan, Lunxi Duan, Hong Zheng
{"title":"CCKBR+ cancer cells contribute to the intratumor heterogeneity of gastric cancer and confer sensitivity to FOXO inhibition","authors":"Zhenya Tan, Ke Pan, Minqiong Sun, Xianzhu Pan, Zhi Yang, Zhiling Chang, Xue Yang, Jicheng Zhu, Li Zhan, Yakun Liu, Xiaofei Li, Keqiong Lin, Lin Chen, Hui Mo, Wei Luo, Chen Kan, Lunxi Duan, Hong Zheng","doi":"10.1038/s41418-024-01360-z","DOIUrl":"10.1038/s41418-024-01360-z","url":null,"abstract":"The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 10","pages":"1302-1317"},"PeriodicalIF":13.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Adapting cytoskeleton-mitochondria patterning with myocyte differentiation by promyogenic PRR33.","authors":"Xuyang Fu, Feng Zhang, Xiaoxuan Dong, Linbin Pu, Yan Feng, Yang Xu, Feng Gao, Tian Liang, Jianmeng Kang, Hongke Sun, Tingting Hong, Yunxia Liu, Hongmei Zhou, Jun Jiang, Deling Yin, Xinyang Hu, Da-Zhi Wang, Jian Ding, Jinghai Chen","doi":"10.1038/s41418-024-01363-w","DOIUrl":"https://doi.org/10.1038/s41418-024-01363-w","url":null,"abstract":"<p><p>Coordinated cytoskeleton-mitochondria organization during myogenesis is crucial for muscle development and function. Our understanding of the underlying regulatory mechanisms remains inadequate. Here, we identified a novel muscle-enriched protein, PRR33, which is upregulated during myogenesis and acts as a promyogenic factor. Depletion of Prr33 in C2C12 represses myoblast differentiation. Genetic deletion of Prr33 in mice reduces myofiber size and decreases muscle strength. The Prr33 mutant mice also exhibit impaired myogenesis and defects in muscle regeneration in response to injury. Interactome and transcriptome analyses reveal that PRR33 regulates cytoskeleton and mitochondrial function. Remarkably, PRR33 interacts with DESMIN, a key regulator of cytoskeleton-mitochondria organization in muscle cells. Abrogation of PRR33 in myocytes substantially abolishes the interaction of DESMIN filaments with mitochondria, leading to abnormal intracellular accumulation of DESMIN and mitochondrial disorganization/dysfunction in myofibers. Together, our findings demonstrate that PRR33 and DESMIN constitute an important regulatory module coordinating mitochondrial organization with muscle differentiation.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ruiqi Yu, Hong Han, Shuxian Chu, Liping Qin, Mengying Du, Yanyan Ma, Yufeng Wang, Wei Jiang, Yu Song, Yongxin Zou, Molin Wang, Qiao Liu, Baichun Jiang, Yaoqin Gong, Gongping Sun
{"title":"Cullin 4B-RING E3 ligase negatively regulates the immunosuppressive capacity of mesenchymal stem cells by suppressing iNOS.","authors":"Ruiqi Yu, Hong Han, Shuxian Chu, Liping Qin, Mengying Du, Yanyan Ma, Yufeng Wang, Wei Jiang, Yu Song, Yongxin Zou, Molin Wang, Qiao Liu, Baichun Jiang, Yaoqin Gong, Gongping Sun","doi":"10.1038/s41418-024-01359-6","DOIUrl":"https://doi.org/10.1038/s41418-024-01359-6","url":null,"abstract":"<p><p>Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-β signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-β signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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