Research Square最新文献

{"title":"The Glucose Transporter 5 Enhances CAR-T Cell Metabolic Function and Anti-tumour Durability","authors":"Roddy S. O’Connor, Bakir Valentić, Andre Kelly, Alexander Shestov, Zhiyang Gan, Feng Shen, Adam Chatoff, Alison Jaccard, Claudia V Crispim, John Scholler, Simon Heeke, Nathaniel Snyder, S. Ghassemi, Nicholas Jones, Saar Gill","doi":"10.21203/rs.3.rs-4342820/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4342820/v1","url":null,"abstract":"Abstract Activated T cells undergo a metabolic shift to aerobic glycolysis to support the energetic demands of proliferation, differentiation, and cytolytic function. Transmembrane glucose flux is facilitated by glucose transporters (GLUT) that play a vital role in T cell metabolic reprogramming and anti-tumour function. GLUT isoforms are regulated at the level of expression and subcellular distribution. GLUTs also display preferential selectivity for carbohydrate macronutrients including glucose, galactose, and fructose. GLUT5, which selectively transports fructose over glucose, has never been explored as a genetic engineering strategy to enhance CAR-T cells in fructose-rich tumour environments. Fructose levels are significantly elevated in the bone marrow and the plasma of acute myeloid leukaemia (AML) patients. Here, we demonstrate that the expression of wild-type GLUT5 restores T cell metabolic fitness in glucose-free, high fructose conditions. We find that fructose supports maximal glycolytic capacity and ATP replenishment rates in GLUT5-expressing T cells. Using steady state tracer technology, we show that 13C6 fructose supports glycolytic reprogramming and TCA anaplerosis in CAR-T cells undergoing log phase expansion. In cytotoxicity assays, GLUT5 rescues T cell cytolytic function in glucose-free medium. The fructose/GLUT5 metabolic axis also supports maximal migratory velocity, which provides mechanistic insight into why GLUT5-expressing CAR-Ts have superior effector function as they undergo “hit-and-run” serial killing. These findings translate to superior anti-tumour function in a xenograft model of AML. In fact, we found that GLUT5 enhances CAR-T cell anti-tumour function in vivo without any need for fructose intervention. Accordingly, we hypothesize that GLUT5 is sufficient to enhance CAR-T resilience by increasing the cells’ competitiveness for glucose at physiologic metabolite levels. Our findings have immediate translational relevance by providing the first evidence that GLUT5 confers a competitive edge in a fructose-enriched milieu, and is a novel approach to overcome glucose depletion in hostile tumour microenvironments (TMEs).","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"15 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of the JAK/STAT Pathway Inhibits Neuroinflammation in the Line 61-PFF Mouse Model of Parkinson’s Disease","authors":"Huixian Hong, Yong Wang, Marissa Menard, Jessica A. Buckley, Lianna Zhou, Laura Volpicelli-Daley, David Standaert, Hongwei Qin, Etty N. Benveniste","doi":"10.21203/rs.3.rs-4307273/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4307273/v1","url":null,"abstract":"Abstract Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of a-synuclein (a-Syn) into insoluble aggregates called Lewy pathology. The Line 61 a-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human a-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human a-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-a-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-a-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4 + T-cells, CD8 + T-cells, CD19 + B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45 + cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1 , H2-Aa , H2-Ab1 , and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf , Il1b , C1qa , and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"64 s295","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141003147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Faster Club Hockey Athletes Have Reduced Upper Leg Muscular Co-contraction During Maximal-Speed Sprinting","authors":"Jason Williams, Joseph C. Watso","doi":"10.21203/rs.3.rs-4283161/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4283161/v1","url":null,"abstract":"Abstract Background Most electromyographic (EMG) data for muscular activation patterns during ambulation is limited to older adults with existing chronic disease(s) walking at slow velocities. However, we know much less about the lower extremity muscle co-contraction patterns during sprinting and its relation to running velocity (i.e., performance). Therefore, we compared lower extremity muscular activation patterns during sprinting between slower and faster collegiate club hockey athletes. We hypothesized that faster athletes would have lower EMG-assessed co-contraction index (CCI) values in the lower extremities during over-ground sprinting. Results Twenty-two males (age = 21[1] yrs (median[IQR]); body mass = 77.1 ± 8.6 kg (mean ± SD)) completed two 20-m over-ground sprints with concomitant EMG and asynchronous force plate testing. We split participants using median running velocity (FAST: 8.5 ± 0.3 vs. SLOW: 7.7 ± 0.3 Conclusions m/s, p  < 0.001). Faster athletes had lower CCI between the rectus femoris and biceps femoris (group: p  = 0.05), particularly during the late swing phase of the gait cycle (post hoc p  = 0.02). In agreement with our hypothesis, we found lower CCI values in the upper leg musculature during maximal-speed over-ground sprinting. These data from collegiate club hockey athletes corroborate other reports in clinical populations that the coordination between the rectus femoris and biceps femoris is associated with linear over-ground sprinting velocity.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"29 44","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fecal Carriage of Multidrug-Resistant Organisms Increases the Risk of Hepatic Encephalopathy in Cirrhotic Patients: Insights from Gut Microbiota and Metabolite Features","authors":"Peishan Wu, Pei-Chang Lee, Tien-En Chang, Y. Hsieh, Jen-Jie Chiou, Chao-Hsiung Lin, Yi-Long Huang, Yi-Tsung Lin, Teh-Ia Huo, Bernd Schnabl, Kuei-Chuan Lee, Ming-Chih Hou","doi":"10.21203/rs.3.rs-4328129/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4328129/v1","url":null,"abstract":"Abstract Background Impact of fecal colonization by multidrug-resistant organisms (MDROs) on changes in gut microbiota and associated metabolites, as well as its role in cirrhosis-associated outcomes, has not been thoroughly investigated. Methods Eighty-eight cirrhotic patients and 22 healthy volunteers were prospectively enrolled with analysis conducted on plasma metabolites, fecal MDROs, and microbiota. Patients were followed for a minimum of one year. Predictive factors for cirrhosis-associated outcomes were identified using Cox proportional hazards regression models, and risk factors for fecal MDRO carriage were assessed using logistic regression model. Correlations between microbiota and metabolic profiles were evaluated through Spearman's rank test. Results Twenty-nine (33%) cirrhotic patients exhibited MDRO carriage, with a notably higher rate of hepatic encephalopathy (HE) in MDRO carriers (20.7% vs. 3.2%, p  = 0.008). Cox regression analysis identified higher serum lipopolysaccharide levels and fecal MDRO carriage as predictors for HE development. Logistic regression analysis showed that MDRO carriage is an independent risk factor for developing HE. Microbiota analysis showed a significant dissimilarity of fecal microbiota between cirrhotic patients with and without MDRO carriage ( p  = 0.033). Thirty-two metabolites exhibiting significantly different expression levels among healthy controls, cirrhotic patients with and without MDRO carriage were identified. Six of the metabolites showed correlation with specific bacterial taxa expression in MDRO carriers, with isoaustin showing significantly higher levels in MDRO carriers experiencing HE compared to those who did not. Conclusion Fecal MDRO carriage is associated with altered gut microbiota, metabolite modulation, and an elevated risk of HE occurrence within a year.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"57 1‐2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141002599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Personality and Self-efficacy for Illness Management in Cancer","authors":"Tristen Peyser, Laura M. Perry, Brenna Mossman, Kenneth Xu, Seowoo Kim, James B. Moran, Michael Hoerger","doi":"10.21203/rs.3.rs-4289523/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4289523/v1","url":null,"abstract":"Abstract Objectives Self-efficacy for illness management is increasingly recognized as important for outcomes in cancer. We examined whether The Big Five personality dimensions were associated with self-efficacy for illness management and hypothesized that patients who were less neurotic and more conscientious would have better self-efficacy. Methods Adults with cancer completed a cross-sectional survey that included the Mini-International Personality Item Pool (IPIP) and three subscales of the Patient-Reported Outcomes Measurement Information System (PROMIS) Self-Efficacy for Chronic Conditions: managing emotions, managing symptoms, and managing treatment and medication. Linear regressions were used to test the hypotheses, while controlling for covariates. Results The personality and PROMIS self-efficacy measures demonstrated good evidence of reliability (median Cronbach’s alpha = .78, range of .69-.92) and validity (intercorrelations). As hypothesized, patients who were less neurotic or more conscientious had higher levels of illness self-efficacy overall and on each of the three subscales (all p s < .001). Openness was associated with better self-management of symptoms ( p  = .013) and emotions ( p  = .040). Extraversion was associated with better self-management of emotions ( p  = .024). Conclusions Personality plays a vital role in illness self-efficacy for patients with cancer. Practice Implications: As a part of multidisciplinary care teams, psychosocial experts can use these findings to help patients better manage their illness.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"39 2‐3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141002206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep brain stimulation of the subthalamic nucleus for Parkinson’s disease: A network imaging marker of the treatment response","authors":"Prashin Unadkat, An Vo, Yilong Ma, Shichun Peng, Nha Nguyen, M. Niethammer, Chris C. Tang, V. Dhawan, Ritesh Ramdhani, Albert Fenoy, S. Caminiti, Daniela Perani, D. Eidelberg","doi":"10.21203/rs.3.rs-4178280/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4178280/v1","url":null,"abstract":"Abstract Subthalamic nucleus deep brain stimulation (STN-DBS) alleviates motor symptoms of Parkinson’s disease (PD), thereby improving quality of life. However, quantitative brain markers to evaluate DBS responses and select suitable patients for surgery are lacking. Here, we used metabolic brain imaging to identify a reproducible STN-DBS network for which individual expression levels increased with stimulation in proportion to motor benefit. Of note, measurements of network expression from metabolic and BOLD imaging obtained preoperatively predicted motor outcomes determined after DBS surgery. Based on these findings, we computed network expression in 175 PD patients, with time from diagnosis ranging from 0 to 21 years, and used the resulting data to predict the outcome of a potential STN-DBS procedure. While minimal benefit was predicted for patients with early disease, the proportion of potential responders increased after 4 years. Clinically meaningful improvement with stimulation was predicted in 18.9 – 27.3% of patients depending on disease duration.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"28 48","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141004369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Trauma Severity of Indoor and Outdoor Injurious Falls Requiring Emergency Medical Service Response","authors":"Kathryn G. Burford, Nicole G. Itzkowitz, R. Crowe, Henry E. Wang, Alexander X Lo, Andrew G. Rundle","doi":"10.21203/rs.3.rs-4202941/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4202941/v1","url":null,"abstract":"Abstract Background : Injurious falls represent a significant public health burden. Research and polices have primarily focused on falls occurring indoors despite evidence that outdoor falls account for 47-58% of all falls requiring some medical attention. This study compared the clinical trauma severity of indoor versus outdoor injurious falls requiring Emergency Medical Services (EMS) response. Methods: Using the 2019 National Emergency Medical Services Information System (NEMSIS) dataset, we identified the location of patients injured from falls that required EMS response. We classified injury severity using 1) the Revised Trauma Score for Triage (T-RTS): ≤ 11 indicated the need for transport to a Trauma Center; 2) Glasgow Coma Scale (GCS): ≤8 and 9–12 indicated moderate and severe neurologic injury; and 3) patient clinical acuity by EMS: Dead, Critical, Emergent, Low. Results : Of 1,854,909 encounters for patients with injurious falls, the vast majority occurred indoors ( n =1,596,860) compared to outdoors ( n =152,994). The proportions of patients with moderate or severe GCS scores, were comparable between those with indoor falls (3.0%) and with outdoor falls on streets or sidewalks (3.8%), T-RTS scores indicating need for transport to a Trauma Center (5.2% vs 5.9%) and EMS acuity rated as Emergent or Critical (27.7% vs 27.1%).Injurious falls were more severe among male patients compared to females: and males injured by falling on streets or sidewalks had higher percentages for moderate or severe GCS scores (4.8% vs 3.6%) and T-RTS scores indicating the need for transport to a Trauma Center (7.3% vs 6.5%) compared to indoor falls. Young and middle-aged patients whose injurious falls occurred on streets or sidewalks were more likely to have a T-RTS score indicating the need for Trauma Center care compared to indoor falls among this subgroup. Yet older patients injured by falling indoors were more likely to have a T-RTS score indicating the need for Trauma Center than older patients who fell on streets or sidewalks. Conclusions : There was a similar proportion of patients with severe injurious falls that occurred indoors and on streets or sidewalks. These findings suggest the need to determine outdoor environmental risks for outdoor falls to support location-specific interventions.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"33 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Amplification of Mediator Subunit 30 Redirects the MYC Transcriptional Program and Oncogenesis","authors":"Chunyu Jin, Linjie Zhao, Guofeng Zhao, Yujia Liu, Wubin Ma, Shenghong Ma, Likun Yao, Yuan Liu, Qiulian Wu, Huairui Yuan, Kailin Yang, K. Ohgi, Jeremy N. Rich, Michael G. Rosenfeld","doi":"10.21203/rs.3.rs-4326418/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4326418/v1","url":null,"abstract":"Abstract Understanding the molecular mechanisms underlying tumorigenesis is crucial for developing effective cancer therapies. Here, we investigate the co-amplification of MED30 and MYC across diverse cancer types and its impact on oncogenic transcriptional programs. Transcriptional profiling of MYC and MED30 single or both overexpression/amplification revealed the over amount of MED30 lead MYC to a new transcriptional program that associate with poor prognosis. Mechanistically, MED30 overexpression/amplification recruits other Mediator components and binding of MYC to a small subset of novel genomic regulatory sites, changing the epigenetic marks and inducing the formation of new enhancers, which drive the expression of target genes crucial for cancer progression. In vivo studies in pancreatic ductal adenocarcinoma (PDAC) further validate the oncogenic potential of MED30, as its overexpression promotes tumor growth and can be attenuated by knockdown of MYC. Using another cancer type as an example, MED30 knockdown reduces tumor growth particularly in MYC high-expressed glioblastoma (GBM) cell lines. Overall, our study elucidates the critical role of MED30 overexpression in orchestrating oncogenic transcriptional programs and highlights its potential as a therapeutic target for MYC-amplified cancer.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"44 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral 8-aminoguanine against age-related retinal degeneration","authors":"Yuanyuan Chen, Abhishek Vats, Yibo Xi, Amanda Wolf-Johnston, Owen D. Clinger, Riley K. Arbuckle, Chase D. Dermond, Jonathan Li, Donna Stolze, J. Sahel, Edwin Jackson, Lori Birder","doi":"10.21203/rs.3.rs-4022389/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4022389/v1","url":null,"abstract":"Abstract Visual decline in the elderly is often attributed to retinal aging, which predisposes the tissue to pathologies such as age-related macular degeneration. Currently, effective oral pharmacological interventions for retinal degeneration are limited. We present a novel oral intervention, 8-aminoguanine (8-AG), targeting age-related retinal degeneration, utilizing the aged Fischer 344 rat model. A low-dose 8-AG regimen (5 mg/kg body weight) via drinking water, beginning at 22 months for 8 weeks, demonstrated significant retinal preservation. This was evidenced by increased retinal thickness, improved photoreceptor integrity, and enhanced electroretinogram responses. 8-AG effectively reduced apoptosis, oxidative damage, and microglial/macrophage activation associated with aging retinae. Age-induced alterations in the retinal purine metabolome, characterized by elevated levels of inosine, hypoxanthine, and xanthine, were partially mitigated by 8-AG. Transcriptomics highlighted 8-AG's anti-inflammatory effects on innate and adaptive immune responses. Extended treatment to 17 weeks further amplified the retinal protective effects. Moreover, 8-AG showed temporary protective effects in the Rho P23H/+ mouse model of retinitis pigmentosa, reducing active microglia/macrophages. Our study positions 8-AG as a promising oral agent against retinal aging. Coupled with previous findings in diverse disease models, 8-AG emerges as a promising anti-aging compound with the capability to reverse common aging hallmarks.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"48 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141007555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cystatin M/E ameliorates bone resorption through increasing osteoclastic cell estrogen influx","authors":"Jin-Ran Chen, Dongzheng Gai, Perry C Caviness, Oxana P. Lazarenko, Jennifer F. Chen, Christopher E Randolph, Zijun Zhang, Yan Cheng, Fumou Sun, Hongwei Xu, Michael Blackburn, Guido J Tricot, John D. Shaughnessy, Fenghuang Zhan","doi":"10.21203/rs.3.rs-4313179/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4313179/v1","url":null,"abstract":"Abstract In multiple myeloma (MM), increased osteoclast differentiation leads to the formation of osteolytic lesions in most MM patients. Bisphosphonates, such as zoledronic acid (ZA), are used to ameliorate bone resorption, but due to risk of serious side effects as well as the lack of repair of existing lesions, novel anti-bone resorption agents are required. Previously, the absence of osteolytic lesions in MM was strongly associated with elevated levels of cystatin M/E (CST6), a cysteine protease inhibitor, secreted by MM cells. In this study, both MM- and ovariectomy (OVX)-induced osteoporotic mouse models were used to compare the effects of recombinant mouse CST6 (rmCst6) and ZA on preventing bone loss. µCT showed that rmCst6 and ZA had similar effects on improving percent bone volume, and inhibited differentiation of non-adherent bone marrow cells into mature osteoclasts. Single-cell RNA sequencing showed that rmCst6 and not ZA treatment reduced bone marrow macrophage percentage in the MM mouse model compared to controls. Protein and mRNA arrays showed that both rmCst6 and ZA significantly inhibit OVX-induced expression of inflammatory cytokines. For OVX mice, ERα protein expression in bone was brought to sham surgery level by only rmCst6 treatments. rmCst6 significantly increased mRNA and protein levels of ERα and significantly increased total intracellular estrogen concentrations for ex vivo osteoclast precursor cell cultures. Based on these results, we conclude that CST6 improves MM or OVX bone loss models by increasing the expression of estrogen receptors as well as the intracellular estrogen concentration in osteoclast precursors, inhibiting their maturation.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"84 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}