Bone ResearchPub Date : 2024-05-29DOI: 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
{"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":null,"pages":null},"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}
{"title":"Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3.","authors":"Bowen Fu, Jianlin Shen, Xuenong Zou, Nian Sun, Ze Zhang, Zengping Liu, Canjun Zeng, Huan Liu, Wenhua Huang","doi":"10.1038/s41413-024-00333-9","DOIUrl":"10.1038/s41413-024-00333-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11126418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis","authors":"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","doi":"10.1038/s41413-024-00336-6","DOIUrl":"https://doi.org/10.1038/s41413-024-00336-6","url":null,"abstract":"<p>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 <i>B. fragilis</i> than DBA/1J mice and RA patients. Transplantation of <i>B. fragilis</i> prevents CIA in DBA/1J mice. We identify that <i>B. fragilis</i> 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 <i>B. fragilis</i> or propionate could be an alternative or complementary approach to the current therapies.</p><figure></figure>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085623","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}
Bone ResearchPub Date : 2024-05-20DOI: 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
{"title":"Author Correction: FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells.","authors":"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","doi":"10.1038/s41413-024-00339-3","DOIUrl":"10.1038/s41413-024-00339-3","url":null,"abstract":"","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bone ResearchPub Date : 2024-05-15DOI: 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
{"title":"RUFY4 deletion prevents pathological bone loss by blocking endo-lysosomal trafficking of osteoclasts.","authors":"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","doi":"10.1038/s41413-024-00326-8","DOIUrl":"10.1038/s41413-024-00326-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":14.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11094054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections","authors":"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","doi":"10.1038/s41413-024-00332-w","DOIUrl":"https://doi.org/10.1038/s41413-024-00332-w","url":null,"abstract":"<p>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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919629","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}
Bone ResearchPub Date : 2024-05-07DOI: 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
{"title":"Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration","authors":"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","doi":"10.1038/s41413-024-00324-w","DOIUrl":"https://doi.org/10.1038/s41413-024-00324-w","url":null,"abstract":"<p>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<sup>+</sup> macrophages, RGCC<sup>+</sup> endothelial cells, ACKR1<sup>+</sup> endothelial cells and ADAM12<sup>+</sup> fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2<sup>+</sup> macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2<sup>+</sup> macrophages migration at the injured peritendinous site by transplantation of bone marrow from <i>Lysm-Cre;R26R</i><sup><i>tdTomato</i></sup> mice to lethally irradiated <i>Ackr1</i><sup><i>−/−</i></sup> mice (<i>Ackr1</i><sup><i>−/−</i></sup> chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2<sup>+</sup> macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2<sup>+</sup> 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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845417","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}
Bone ResearchPub Date : 2024-05-06DOI: 10.1038/s41413-024-00334-8
Yan Luo, Shengyuan Zheng, Wenfeng Xiao, Hang Zhang, Yusheng Li
{"title":"Pannexins in the musculoskeletal system: new targets for development and disease progression","authors":"Yan Luo, Shengyuan Zheng, Wenfeng Xiao, Hang Zhang, Yusheng Li","doi":"10.1038/s41413-024-00334-8","DOIUrl":"https://doi.org/10.1038/s41413-024-00334-8","url":null,"abstract":"<p>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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845122","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}
Bone ResearchPub Date : 2024-04-15DOI: 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}
{"title":"Sorafenib inhibits ossification of the posterior longitudinal ligament by blocking LOXL2-mediated vascularization","authors":"Longqing Wang, Wenhao Jiang, Siyuan Zhao, Dong Xie, Qing Chen, Qi Zhao, Hao Wu, Jian Luo, Lili Yang","doi":"10.1038/s41413-024-00327-7","DOIUrl":"https://doi.org/10.1038/s41413-024-00327-7","url":null,"abstract":"<p>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 <i>enpp1</i> 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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140541800","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}