JBMR Plus最新文献_第5页

Chromatin accessibility and epigenetic DNA modifications in CKD osteoblasts: a study of bone and osteoblasts from pediatric patients with chronic kidney disease 慢性肾脏病成骨细胞的染色质可及性和表观遗传 DNA 修饰：对慢性肾脏病儿科患者骨骼和成骨细胞的研究

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 DOI: 10.1093/jbmrpl/ziad015

Aline Martin, R. Kawaguchi, Qing Wang, I. Salusky, Renata C Pereira, K. Wesseling-Perry

Maturation defects are intrinsic features of osteoblast lineage cells in CKD patients. These defects persist ex vivo, suggesting that CKD induces epigenetic changes in bone cells. To gain insights into which signaling pathways contribute to CKD-mediated, epigenetically-driven, impairments in osteoblast maturation, we characterized RNA expression and DNA methylation patterns by RNA-Seq and Methylation Epic in primary osteoblasts from 9 adolescent and young adult dialysis patients with end-stage kidney disease and 3 healthy references. ATAC-Seq was also performed on a subset of osteoblasts. Bone matrix protein expression was extracted from iliac crest and evaluated by proteomics. GSEA analysis was used to establish signaling pathways consistently altered in chromatin accessibility, DNA methylation, and RNA expression patterns. Single genes were suppressed in primary osteoblasts using shRNA and mineralization characterized in vitro. The effect of NFAT signaling suppression was also assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) incorporation. We found that signaling pathways critical for osteoblast differentiation were strongly downregulated in CKD osteoblasts. GSEA identified highly significant methylation changes, differential chromatin accessibility, and altered RNA expression in NFAT signaling targets. NFAT inhibition reduced osteoblast proliferation. Combined analysis of osteoblast RNA expression and whole bone matrix composition identified thirteen potential ligand-receptor pairs were identified. In summary, epigenetic changes in CKD osteoblasts associate with altered expression of multiple osteoblast genes and signaling pathways. An increase in NFAT signaling may play a role in impaired CKD osteoblast maturation. Epigenetic changes also associate with an altered bone matrix which may contribute to bone fragility. Further studies are necessary to elucidate the pathways affected by these genetic alterations since elucidating these pathways will be vital to correcting the underlying biology of bone disease in the CKD population.

成熟缺陷是 CKD 患者成骨细胞系细胞的固有特征。这些缺陷在体内外持续存在，表明 CKD 会诱导骨细胞发生表观遗传学变化。为了深入了解哪些信号通路有助于CKD介导的表观遗传学驱动的成骨细胞成熟障碍，我们通过RNA-Seq和甲基化史诗鉴定了9名患有终末期肾病的青少年和年轻成人透析患者以及3名健康参考者的原代成骨细胞的RNA表达和DNA甲基化模式。还对成骨细胞子集进行了 ATAC-Seq。从髂嵴提取骨基质蛋白表达，并通过蛋白质组学进行评估。GSEA 分析用于确定染色质可及性、DNA 甲基化和 RNA 表达模式发生一致改变的信号通路。利用 shRNA 抑制了原发性成骨细胞中的单个基因，并在体外鉴定了矿化特征。我们还使用 3-（4,5-二甲基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2-（4-磺酸苯基）-2H-四氮唑（MTS）掺入法评估了 NFAT 信号抑制的效果。我们发现，在 CKD 成骨细胞中，对成骨细胞分化至关重要的信号通路被强烈下调。GSEA 发现了 NFAT 信号靶点的高度甲基化变化、染色质可及性差异和 RNA 表达改变。抑制 NFAT 可减少成骨细胞的增殖。对成骨细胞 RNA 表达和整个骨基质组成的综合分析确定了 13 对潜在的配体-受体。总之，CKD 成骨细胞的表观遗传学变化与多个成骨细胞基因和信号通路的表达改变有关。NFAT 信号的增加可能是 CKD 成骨细胞成熟受损的原因之一。表观遗传学变化还与骨基质的改变有关，这可能会导致骨质脆弱。有必要开展进一步研究，以阐明受这些基因改变影响的通路，因为阐明这些通路对于纠正 CKD 患者骨病的潜在生物学特性至关重要。

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引用次数: 0

Peripheral canalicular branching is decreased in streptozotocin-induced diabetes and correlates with decreased whole-bone ultimate load and perilacunar elastic work 链脲佐菌素诱导的糖尿病患者外周管腔分支减少，与全骨极限载荷和周缘弹性功的减少有关

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 DOI: 10.1093/jbmrpl/ziad017

Morgan W. Bolger, Tara Tekkey, David H. Kohn

Osteocytes are the most abundant cell type in bone, important for mechanosensation, signaling for bone formation, resorption and osteocytes reside in a complex lacuno-canalicular network (OLCN). Osteocyte signaling is reduced under diabetic conditions, and both type 1 and type 2 diabetes lead to reduced bone turnover, perturbed bone composition and increased fracture risk. We hypothesized this reduced bone turnover and altered bone composition with diabetes is associated with reduced OLCN architecture and connectivity. This study aimed to elucidate: 1) the sequence of OLCN changes with diabetes related to bone turnover, and 2) whether changes to the OLCN are associated with tissue composition and mechanical properties. 12–14 week old male C57BL/6 mice were administered streptozotocin at 50 mg/kg for 5 consecutive days to induce hyperglycemia, sacrificed at baseline (BL), or after being diabetic for 3 (D3), 7 (D7) weeks with age-matched (C3, C7) controls (n = 10–12 per group). Mineralized femoral sections were infiltrated with rhodamine, imaged with confocal microscopy, then the OLCN morphology and topology were characterized and correlated against bone histomorphometry, local and whole bone mechanics and composition. D7 mice exhibited a lower number of peripheral branches relative to C7. The total number of canalicular intersections (nodes) was lower in D3 and D7 relative to BL (p < 0.05 for all) and a reduced bone formation rate (BFR) was observed at D7 vs. C7. The number of nodes explained only 15% of BFR, but 45% of Ct.BV/TV, and 31% of ultimate load. The number of branches explained 30% and 22% of the elastic work at the perilacunar and intracortical region, respectively. Collectively, the reduction in OLCN architecture, and association of OLCN measures with bone turnover, mechanics and composition highlights the relevance of the osteocyte and the OLCN, and a potential therapeutic target for treating diabetic skeletal fragility.

骨细胞是骨骼中最丰富的细胞类型，对机械感觉、骨形成和骨吸收的信号传递非常重要，骨细胞驻留在一个复杂的裂隙-颅骨网络（OLCN）中。在糖尿病条件下，骨细胞信号传导会减少，1 型和 2 型糖尿病都会导致骨转换减少、骨组成紊乱和骨折风险增加。我们假设，糖尿病导致的骨转换减少和骨组成改变与 OLCN 结构和连接性降低有关。本研究旨在阐明：1）OLCN的变化顺序与糖尿病引起的骨转换有关；2）OLCN的变化是否与组织成分和机械性能有关。给 12-14 周大的雄性 C57BL/6 小鼠连续注射 5 天 50 毫克/千克的链脲佐菌素以诱导高血糖，在基线（BL）或糖尿病 3 周（D3）、7 周（D7）后与年龄匹配（C3、C7）的对照组（每组 10-12 只）一起处死。用罗丹明浸润矿化的股骨切片，并用共聚焦显微镜成像，然后描述 OLCN 的形态和拓扑结构，并将其与骨组织形态计量学、局部和整体骨力学及成分相关联。与 C7 小鼠相比，D7 小鼠的外周分支数量较少。与 BL 相比，D3 和 D7 小鼠的管状交叉点（节点）总数较低（P < 0.05），并且观察到 D7 小鼠的骨形成率（BFR）低于 C7 小鼠。节点数只能解释 15%的骨形成率，但能解释 45%的 Ct.BV/TV 和 31%的极限负荷。分支数量分别解释了皮质周围和皮质内区域 30% 和 22% 的弹性功。总之，OLCN结构的减少以及OLCN测量与骨转换、力学和组成的关联突出了骨细胞和OLCN的相关性，以及治疗糖尿病骨骼脆性的潜在治疗目标。

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引用次数: 0

Comparison of physiological and behavioural nutrition-related factors in people with and without adolescent idiopathic scoliosis, from cohort data at 8 to 20 years 从 8 至 20 年的队列数据中比较青少年特发性脊柱侧凸患者和非患者的生理和行为营养相关因素

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 DOI: 10.1093/jbmrpl/ziad013

Phoebe T T Ng, Kylie Tucker, Farah Zahir, M. Izatt, Leon Straker, Andrew Claus

Nutrition-related variables including lower body mass index (BMI), lower bone mineral density (BMD), altered body composition and hormone levels have been reported in adolescent idiopathic scoliosis (AIS). To determine if physiological and behavioural nutrition-related factors differ between people with and without AIS, and to quantify their relationship with AIS, in unbiased cohort sample. BMI, presence of an eating disorder, leptin, adiponectin, BMD, vitamin D, lean mass and fat mass were compared between those with and without AIS at ages 8, 10, 14, 17 and 20 years, and multiple logistic regression was performed between these variables and AIS. Lower total body BMD (median 1.0 g/cm2 vs 1.1 g/cm2, p = 0.03) and lean mass (median 38.8 kg vs 46.0 kg, p = 0.04) at age 20 years were observed in those with AIS compared to those without scoliosis. At age 20, the odds of AIS were 3.23 times higher for adolescents with an eating disorder compared to those with no eating disorder (95%CI[1.02, 8.63)) when adjusted for BMI. Every 1 kg/m2 increase in BMI decreased the odds of AIS by 0.88 times (95%CI[0.76 to 0.98]) after adjusting for eating disorder diagnosis. Lower BMI in mid-adolescence and presence of eating disorder outcomes, lower BMD and lower lean mass in late adolescence were associated with the presence of AIS. Current data do not explain the mechanisms for these associations, but suggest that serum leptin, adiponectin and vitamin D are unlikely to be contributing factors. Conclusive determination of the prevalence of eating disorders in AIS will require further studies with larger sample sizes.

据报道，青少年特发性脊柱侧弯症（AIS）患者的营养相关变量包括较低的体重指数（BMI）、较低的骨矿物质密度（BMD）、身体成分和激素水平的改变。目的是在无偏见的队列样本中确定特发性脊柱侧弯症患者和非特发性脊柱侧弯症患者的生理和行为营养相关因素是否存在差异，并量化这些因素与特发性脊柱侧弯症的关系。研究人员比较了 8、10、14、17 和 20 岁 AIS 患者和非 AIS 患者的体重指数、是否存在饮食失调、瘦素、脂肪连通素、BMD、维生素 D、瘦肉质量和脂肪质量，并对这些变量与 AIS 之间的关系进行了多元逻辑回归。与没有脊柱侧弯的人相比，AIS 患者在 20 岁时的全身 BMD（中位数为 1.0 g/cm2 vs 1.1 g/cm2，p = 0.03）和瘦体重（中位数为 38.8 kg vs 46.0 kg，p = 0.04）较低。经调整体重指数后，20 岁时患有饮食失调的青少年与未患有饮食失调的青少年相比，患 AIS 的几率要高出 3.23 倍（95%CI[1.02, 8.63]）。在对饮食失调诊断进行调整后，体重指数每增加1 kg/m2，AIS几率就会降低0.88倍（95%CI[0.76至0.98]）。青春期中期较低的体重指数、存在饮食失调的结果、青春期后期较低的骨密度和较低的瘦体重与 AIS 的存在有关。目前的数据无法解释这些关联的机制，但表明血清瘦素、脂肪连接素和维生素 D 不太可能是诱因。要最终确定AIS中饮食失调的患病率，还需要进行更多的样本研究。

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引用次数: 0

Fracture discrimination capability of ulnar flexural rigidity measured via cortical bone mechanics technology: study protocol for the Stronger study 通过皮质骨力学技术测量尺骨挠曲刚度的骨折辨别能力："更强大 "研究的研究方案

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 DOI: 10.1093/jbmrpl/ziad002

Stuart J Warden, Andrew Dick, Janet E Simon, Todd M. Manini, David W. Russ, Charalampos Lyssikatos, Leatha A. Clark, Brian C. Clark

Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility (i.e., weakness) and an increased risk for fracture. The current standard for assessing bone health and diagnosing osteoporosis is dual-energy x-ray absorptiometry (DXA), which quantifies areal bone mineral density (BMD), typically at the hip and spine. However, DXA-derived BMD assesses only one component of bone health and is notably limited in evaluating bone strength, a critical factor in fracture resistance. Although multifrequency vibration analysis can quickly and painlessly assay bone strength, there has been limited success in advancing a device of this nature. Recent progress has resulted in the development of Cortical Bone Mechanics Technology (CBMT), which conducts a dynamic 3-point bending test to assess the flexural rigidity (EI) of ulnar cortical bone. Data indicates that ulnar EI accurately estimates ulnar whole bone strength and provides unique and independent information about cortical bone compared to DXA-derived BMD. Consequently, CBMT has the potential to address a critical unmet need: better identification of patients with diminished bone strength who are at high risk of experiencing a fragility fracture. However, the clinical utility of CBMT-derived EI has not yet been demonstrated. We have designed a clinical study to assess the accuracy of CBMT-derived ulnar EI in discriminating post-menopausal women who have suffered a fragility fracture from those who have not. These data will be compared to DXA-derived peripheral and central measures of BMD obtained from the same subjects. In this article, we describe the study protocol for this multi-center fracture discrimination study (The STRONGER Study).

骨质疏松症的特点是骨量低和骨组织结构退化，导致骨质脆弱（即软弱无力）和骨折风险增加。目前评估骨骼健康和诊断骨质疏松症的标准是双能 X 射线吸收测量法（DXA），它可以量化骨矿密度（BMD），通常是髋关节和脊柱的骨矿密度。然而，DXA 导出的 BMD 仅能评估骨骼健康的一个组成部分，在评估骨强度（抗骨折的一个关键因素）方面具有明显的局限性。虽然多频振动分析可以快速、无痛地检测骨强度，但在推广此类设备方面取得的成功却很有限。最近的进展是开发出了皮质骨力学技术（CBMT），该技术可进行动态三点弯曲测试，以评估尺骨皮质骨的弯曲刚度（EI）。数据表明，尺骨 EI 能准确估算尺骨整体强度，与 DXA 导出的 BMD 相比，它能提供独特而独立的皮质骨信息。因此，CBMT 有可能满足一项关键的未满足需求：更好地识别骨强度减弱且有发生脆性骨折高风险的患者。然而，CBMT 衍生 EI 的临床实用性尚未得到证实。我们设计了一项临床研究，以评估 CBMT 导出的尺骨 EI 在区分绝经后脆性骨折妇女和未发生脆性骨折妇女方面的准确性。这些数据将与从同一受试者身上获得的 DXA 导出的外周和中心 BMD 测量值进行比较。在本文中，我们将介绍这项多中心骨折鉴别研究（STRONGER 研究）的研究方案。

{"title":"Fracture discrimination capability of ulnar flexural rigidity measured via cortical bone mechanics technology: study protocol for the Stronger study","authors":"Stuart J Warden, Andrew Dick, Janet E Simon, Todd M. Manini, David W. Russ, Charalampos Lyssikatos, Leatha A. Clark, Brian C. Clark","doi":"10.1093/jbmrpl/ziad002","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad002","url":null,"abstract":"\u0000 Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility (i.e., weakness) and an increased risk for fracture. The current standard for assessing bone health and diagnosing osteoporosis is dual-energy x-ray absorptiometry (DXA), which quantifies areal bone mineral density (BMD), typically at the hip and spine. However, DXA-derived BMD assesses only one component of bone health and is notably limited in evaluating bone strength, a critical factor in fracture resistance. Although multifrequency vibration analysis can quickly and painlessly assay bone strength, there has been limited success in advancing a device of this nature. Recent progress has resulted in the development of Cortical Bone Mechanics Technology (CBMT), which conducts a dynamic 3-point bending test to assess the flexural rigidity (EI) of ulnar cortical bone. Data indicates that ulnar EI accurately estimates ulnar whole bone strength and provides unique and independent information about cortical bone compared to DXA-derived BMD. Consequently, CBMT has the potential to address a critical unmet need: better identification of patients with diminished bone strength who are at high risk of experiencing a fragility fracture. However, the clinical utility of CBMT-derived EI has not yet been demonstrated. We have designed a clinical study to assess the accuracy of CBMT-derived ulnar EI in discriminating post-menopausal women who have suffered a fragility fracture from those who have not. These data will be compared to DXA-derived peripheral and central measures of BMD obtained from the same subjects. In this article, we describe the study protocol for this multi-center fracture discrimination study (The STRONGER Study).","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"45 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139450579","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}

引用次数: 0

Pten knockout in mouse preosteoblasts leads to changes in bone turnover and strength 小鼠前成骨细胞中的 Pten 基因敲除导致骨转换和骨强度发生变化

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 DOI: 10.1093/jbmrpl/ziad016

J. Lorenz, Sandy Richter, Anna S. Kirstein, Florentien Kolbig, Michèle Nebe, Marco Schulze, Wieland Kiess, Ingo Spitzbarth, Nora Klöting, D. Le Duc, Ulrike Baschant, A. Garten

Bone development and remodeling are controlled by the phosphoinositide-3-kinase (Pi3k) signaling pathway. We investigated the effects of downregulation of phosphatase and tensin homolog (Pten), a negative regulator of Pi3k signaling, in a mouse model of Pten deficiency in preosteoblasts. We aimed to identify mechanisms that are involved in the regulation of bone turnover and are linked to bone disorders. Femora, tibiae, and bone marrow stromal cells (BMSCs) isolated from mice with a conditional deletion of Pten (Pten cKO) in Osterix/Sp7 expressing osteoprogenitor cells were compared to Cre negative controls. Bone phenotyping was performed by μCT measurements, bone histomorphometry, quantification of bone turnover markers CTX and P1NP and 3-point bending test. Proliferation of BMSCs was measured by counting nuclei and Ki-67-stained cells. In vitro, osteogenic differentiation capacity was determined by ALP staining, as well as by detecting gene expression of osteogenic markers. BMSCs from Pten cKO mice were functionally different from control BMSCs. Osteogenic markers were increased in BMSCs derived from Pten cKO mice, while Pten protein expression was lower and Akt phosphorylation was increased. We detected a higher trabecular bone volume and an altered cortical bone morphology in Pten cKO bones with a progressive decrease in bone and tissue mineral density. Pten cKO bones displayed fewer osteoclasts and more osteoblasts (p = 0.00095) per trabecular bone surface and a higher trabecular bone formation rate. Biomechanical analysis revealed a significantly higher bone strength (p = 0.00012 for males) and elasticity of Pten cKO femora. On the cellular level, both proliferation and osteogenic differentiation capacity of Pten cKO BMSCs were significantly increased compared to controls. Our findings suggest that Pten knockout in osteoprogenitor cells increases bone stability and elasticity by increasing trabecular bone mass and leads to increased proliferation and osteogenic differentiation of bone marrow stromal cells.

骨骼的发育和重塑受磷酸肌醇-3-激酶（Pi3k）信号通路的控制。我们研究了下调磷酸酶和天丝蛋白同源物（Pten）的影响，Pten是Pi3k信号传导的负调控因子。我们的目的是找出参与调节骨转换并与骨疾病相关的机制。我们将从 Osterix/Sp7 表达骨生成细胞中条件性缺失 Pten（Pten cKO）的小鼠体内分离出的股骨、胫骨和骨髓基质细胞（BMSCs）与 Cre 阴性对照组进行了比较。通过μCT测量、骨组织形态测量、骨转换标记物CTX和P1NP定量以及三点弯曲试验对骨表型进行了分析。BMSCs 的增殖通过细胞核计数和 Ki-67 染色细胞进行测量。在体外，通过ALP染色和检测成骨标志物的基因表达来确定成骨分化能力。Pten cKO 小鼠的 BMSCs 在功能上与对照组 BMSCs 不同。Pten cKO 小鼠的 BMSCs 中成骨细胞标志物增加，而 Pten 蛋白表达降低，Akt 磷酸化增加。我们在 Pten cKO 小鼠骨骼中检测到较高的骨小梁体积和改变的皮质骨形态，骨和组织矿物质密度逐渐降低。Pten cKO骨骼的每个骨小梁表面显示出较少的破骨细胞和较多的成骨细胞（p = 0.00095），骨小梁骨形成率较高。生物力学分析表明，Pten cKO 股骨的骨强度（男性 p = 0.00012）和弹性明显更高。在细胞水平上，与对照组相比，Pten cKO BMSCs 的增殖和成骨分化能力均显著提高。我们的研究结果表明，骨生成细胞中的Pten基因敲除可通过增加骨小梁质量来提高骨的稳定性和弹性，并导致骨髓基质细胞的增殖和成骨分化能力增强。

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引用次数: 0

Staphylococcus aureus Panton-Valentine Leukocidin worsens acute implant-associated osteomyelitis in humanized BRGSF mice 金黄色葡萄球菌潘通-瓦伦丁白细胞介素会加重人源化 BRGSF 小鼠急性植入物相关骨髓炎的病情

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 DOI: 10.1093/jbmrpl/ziad005

Marloes I. Hofstee, C. Siverino, Motoo Saito, Himanshu Meghwani, James Tapia-Dean, Samson Arveladze, M. Hildebrand, Javier Rangel-Moreno, M. Riool, S. Zeiter, S. Zaat, T. F. Moriarty, G. Muthukrishnan

Staphylococcus aureus is the most common pathogen that causes implant-associated osteomyelitis, a clinically incurable disease. Immune evasion of S. aureus relies on various mechanisms to survive within the bone niche, including the secretion of leukotoxins such as Panton-Valentine leukocidin (PVL). PVL is a pore-forming toxin exhibiting selective human tropism for C5a receptors (C5aR1 and C5aR2) on neutrophils, monocytes, and macrophages. PVL is an important virulence determinant in lung, skin and soft tissue infections. The involvement of PVL in S. aureus pathogenesis during bone infections has not been studied extensively yet. To study this, humanized BALB/c Rag2−/−Il2rg−/−SirpaNODFlk2−/− (huBRGSF) mice were subjected to transtibial implant-associated osteomyelitis with community-acquired methicillin-resistant S. aureus (CA-MRSA) USA300 wild type strain (WT), an isogenic mutant lacking lukF/S-PV (Δpvl), or complemented mutant (Δpvl+pvl). Three days post-surgery, Δpvl-infected huBRGSF mice had a less severe infection compared to WT-infected animals as characterized by 1) improved clinical outcomes, 2) lower ex vivo bacterial bone burden, 3) absence of staphylococcal abscess communities (SACs) in their bone marrow, and 4) compromised MRSA dissemination to internal organs (liver, kidney, spleen, heart). Interestingly, Δpvl-infected huBRGSF mice had fewer human myeloid cells, neutrophils, and HLA-DR+ monocytes in the bone niche compared to WT-infected animals. Expectedly, a smaller fraction of human myeloid cells were apoptotic in the Δpvl-infected huBRGSF animals. Taken together, our study highlights the pivotal role of PVL during acute implant-associated osteomyelitis in humanized mice.

金黄色葡萄球菌是导致植入相关骨髓炎的最常见病原体，这是一种临床上无法治愈的疾病。金黄色葡萄球菌依靠各种机制躲避免疫，以便在骨龛中生存，其中包括分泌白细胞毒素，如潘顿-瓦伦丁白细胞介素（PVL）。PVL 是一种孔隙形成毒素，对中性粒细胞、单核细胞和巨噬细胞上的 C5a 受体（C5aR1 和 C5aR2）具有选择性的人类趋附性。PVL 是肺部、皮肤和软组织感染的重要毒力决定因素。关于 PVL 在骨感染过程中参与金黄色葡萄球菌致病机理的研究尚未广泛开展。为了研究这个问题，我们用社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）USA300野生型菌株（WT）、缺乏lukF/S-PV的同源突变体（Δpvl）或互补突变体（Δpvl+pvl）对人源化BALB/c Rag2-/-Il2rg-/-SirpaNODFlk2-/-（huBRGSF）小鼠进行了经胫骨植入相关性骨髓炎试验。手术后三天，与 WT 感染的小鼠相比，Δpvl 感染的 huBRGSF 小鼠的感染程度较轻，其特点是：1）临床结果有所改善；2）体内外细菌骨负荷较低；3）骨髓中没有葡萄球菌脓肿群落（SAC）；4）MRSA 向内脏（肝、肾、脾、心脏）的扩散受到影响。有趣的是，与 WT 感染的小鼠相比，Δpvl 感染的 huBRGSF 小鼠骨龛中的人类髓系细胞、中性粒细胞和 HLA-DR+ 单核细胞较少。因此，在感染了Δpvl 的 huBRGSF 动物中，凋亡的人髓系细胞的比例也较小。综上所述，我们的研究强调了 PVL 在人源化小鼠急性植入物相关骨髓炎中的关键作用。

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引用次数: 0

Bone-turnover variability via progenitor feedback 通过祖先反馈实现骨转换的可变性

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 DOI: 10.1093/jbmrpl/ziad003

Young Kwan Kim, Yoshitaka Kameo, Sakae Tanaka, Taiji Adachi

Bone turnover markers (BTMs) are commonly used in osteoporosis treatment as indicators of cell activities of bone-resorbing osteoclasts and bone-forming osteoblasts. The wide variability in their values due to multiple factors, such as aging and diseases, makes it difficult for physicians to utilize them for clinical decision-making. The progenitors of osteoclasts and osteoblasts are indispensable for a comprehensive interpretation of the variability in BTM values because these upstream progenitors strongly regulate the downstream cell activities of bone turnover. However, understanding the complex interactions among the multiple populations of bone cells is challenging. In this study, we aimed to gain a fundamental understanding of the mechanism by which the progenitor dynamics affect the variability in bone turnover through in silico experiments by exploring the cell dynamics with aging effects on osteoporosis. Negative feedback control driven by the consumptive loss of progenitors prevents rapid bone loss due to excessive bone turnover, and through feedback regulation, aging effects on osteoclast differentiation and osteoclast progenitor proliferation cause variability in the osteoclast and osteoblast activity balance and its temporal transition. By expressing the variability in the bone turnover status, our model describes the individualities of patients based on their clinical backgrounds. Therefore, our model could play a powerful role in assisting tailored treatment and has the potential to resolve the various health problems associated with osteoporosis worldwide.

骨转换标志物（BTMs）是骨质疏松症治疗中常用的骨吸收破骨细胞和骨形成成骨细胞的细胞活性指标。由于受衰老和疾病等多种因素的影响，这些指标的数值变化很大，因此医生很难将其用于临床决策。要全面解释 BTM 值的变化，破骨细胞和成骨细胞的祖细胞是不可或缺的，因为这些上游祖细胞对骨转换的下游细胞活动有很强的调控作用。然而，要了解骨细胞多个种群之间复杂的相互作用具有挑战性。在本研究中，我们旨在通过探索衰老对骨质疏松症影响的细胞动态，通过硅学实验从根本上了解祖细胞动态影响骨转换变化的机制。由祖细胞消耗性丢失驱动的负反馈控制可防止骨转换过度导致的骨量快速丢失，而通过反馈调节，衰老对破骨细胞分化和破骨细胞祖细胞增殖的影响会导致破骨细胞和成骨细胞活性平衡及其时间转换的变异性。通过表达骨转换状态的变异性，我们的模型可以根据患者的临床背景描述其个性。因此，我们的模型可在辅助定制治疗方面发挥强大作用，并有可能解决全球与骨质疏松症相关的各种健康问题。

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引用次数: 0

Assessment of bovine cortical bone fracture behavior using impact microindentation as a surrogate of fracture toughness. 用冲击微压痕法评估牛皮质骨的断裂行为，作为断裂韧性的替代方法。

IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2024-01-04 eCollection Date: 2024-02-01 DOI: 10.1093/jbmrpl/ziad012

Babak Jahani, Rachana Vaidya, James M Jin, Donald A Aboytes, Kaitlyn S Broz, Siva Krothapalli, Bhanuteja Pujari, Walee M Baig, Simon Y Tang

The fracture behavior of bone is critically important for evaluating its mechanical competence and ability to resist fractures. Fracture toughness is an intrinsic material property that quantifies a material's ability to withstand crack propagation under controlled conditions. However, properly conducting fracture toughness testing requires the access to calibrated mechanical load frames and the destructive testing of bone samples, and therefore fracture toughness tests are clinically impractical. Impact microindentation mimicks certain aspects of fracture toughness measurements, but its relationship with fracture toughness remains unknown. In this study, we aimed to compare measurements of notched fracture toughness and impact microindentation in fresh and boiled bovine bone. Skeletally mature bovine bone specimens (n = 48) were prepared, and half of them were boiled to denature the organic matrix, while the other half remained preserved in frozen conditions. All samples underwent a notched fracture toughness test to determine their resistance to crack initiation (K_IC) and an impact microindentation test using the OsteoProbe to obtain the Bone Material Strength index (BMSi). Boiling the bone samples increased the denatured collagen content, while mineral density and porosity remained unaffected. The boiled bones also showed significant reduction in both K_IC (P < .0001) and the average BMSi (P < .0001), leading to impaired resistance of bone to crack propagation. Remarkably, the average BMSi exhibited a high correlation with K_IC (r = 0.86; P < .001). A ranked order difference analysis confirmed the excellent agreement between the 2 measures. This study provides the first evidence that impact microindentation could serve as a surrogate measure for bone fracture behavior. The potential of impact microindentation to assess bone fracture resistance with minimal sample disruption could offer valuable insights into bone health without the need for cumbersome testing equipment and sample destruction.

骨骼的断裂行为对于评估其机械性能和抗断裂能力至关重要。断裂韧性是一种内在的材料属性，可量化材料在受控条件下承受裂纹扩展的能力。然而，正确进行断裂韧性测试需要使用校准过的机械载荷框架和对骨骼样本进行破坏性测试，因此断裂韧性测试在临床上并不实用。冲击微压痕在某些方面模仿了断裂韧性测量，但其与断裂韧性的关系仍不清楚。在这项研究中，我们旨在比较新鲜牛骨和煮沸牛骨的缺口断裂韧性测量值和冲击微压痕测量值。我们制备了骨骼成熟的牛骨标本（n = 48），其中一半通过煮沸使有机基质变性，另一半在冷冻条件下保存。所有样本都进行了缺口断裂韧性测试，以确定其抗开裂性（KIC），并使用 OsteoProbe 进行了冲击微压痕测试，以获得骨材料强度指数（BMSi）。沸煮骨样本会增加变性胶原蛋白的含量，而矿物质密度和孔隙率则不受影响。沸煮后的骨骼还显示出 KIC（P < .0001）和平均 BMSi（P < .0001）的显著降低，导致骨骼抗裂纹扩展的能力减弱。值得注意的是，平均 BMSi 与 KIC 呈高度相关性（r = 0.86；P < .001）。排序差异分析证实了这两种测量方法之间的极佳一致性。这项研究首次证明了冲击微压痕可作为骨断裂行为的替代测量方法。冲击微压痕法可以在尽量不破坏样本的情况下评估骨断裂阻力，无需使用笨重的测试设备和破坏样本，因此可以为了解骨骼健康状况提供有价值的信息。

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JBMR Plus Reviewer list 2023 2023 年 JBMR Plus 评审员名单

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2023-12-19 DOI: 10.1002/jbm4.10844

The ASBMR and the journal Editors are incredibly thankful for the reviewers who volunteer their time for the vital mentoring role of peer reviewer. The following individuals have reviewed for JBMR Plus in the past year and have provided invaluable feedback to help improve submitted papers.Data through November 14, 2022 – October 25, 2023.*Indicates 3 or more reviews completed.**Indicates 5 or more reviews completed.Annette AdamsRiad AkhundovHenry AkinbiAhmed Al Saedi*Imranul AlamMatt AllenCatherine AmbroseNatasha Appelman-DijkstraJohn Asplin*Reggie AuroraUgur AyturkYangjin BaeChelsea BahneyJeannie BaileyRafal BartoszewskiKristen BeaversSanjay BhadadaHarry BlairRobert Blank**Elizabeth BradleyMikkel BrentJacques Brown*Lucas BrunBjoern BuehringEllish BurkeDavid B. Burr*Bjoern BusseJay J. CaoDana CarpenterAlesandra CarrieroJames CassatNaibedya ChattopadhyayChien-Liang Chen*Jin-RanChenJe-Yong ChoiCristiana CiprianiBrian C. ClarkMartine Cohen-SolalAdi Cohen**Mary ColeKelsey CollinsFabio Vasconcellos ComimTim CootesSabrina CorbettaNicola CrabtreeApril CraftCarolyn CrandallJames Cray*Laura CreemersSouad DaamouchRafael de MolonSusan DiemNaomi DirckxSinee DisthabanchongPaola Divieti Pajevic*Kate DuchownyEmma DuncanFlorent ElefteriouKlaus EngelkeDaniel EvansPeter FabianAlberto Falchetti*Charles FarberVirginia FergusonAníbal FerreiraTrine Elisabeth FinnesAntonella Forlino*Andrea FoxMorten FrostSeiji Fukumoto**Dana GaddyGustavo GarletDamian Genetos**Samuel GhatanCharles GinsbergNeil GittoesDavid GoldhamerCorinna GrasemannMatthew Greenblatt*Jennifer GregoryAnne Grethe JurikYaodong Gu*Scott A. GuelcherAnyonya GunturMelanie Haffner-LuntzerDieter HaffnerMark HamrickSarah Hardcastle**Nan HatchAlberto Hidalgo-BravoKevin HoffsethHironori HojoNilsson HolguinMichael HolickKara Holloway-KewKuo-Chin HuangJulie HughesSteven Ing*Alex IrelandCarlos Isales**M. Kassim JavaidKarl JepsenEijiro JimiFjola Johannesdottir*Mark JohnsonHiroshiKajiLamya KarimKurt KennelHa-Neui Kim*Keunyoung KimFrank Ko**Joyce S.B. KohYoshihiro KomatsuSung Hye KongSusan KrumTakuo KubotaLisa LangsetmoChristine LaryMichael LaurentCarole Le Henaff*Ma

ASBMR 和期刊编辑非常感谢审稿人自愿抽出时间担任同行评审这一重要的指导角色。以下人员在过去一年中为《JBMR Plus》进行了审稿，并提供了宝贵的反馈意见，帮助改进所提交的论文。Annette AdamsRiad AkhundovHenry AkinbiAhmed Al Saedi*Imranul AlamMatt AllenCatherine AmbroseNatasha Appelman- DijkstraJohn AsplerDijkstraJohn Asplin*Reggie AuroraUgur AyturkYangjin BaeChelsea BahneyJeannie BaileyRafal BartoszewskiKristen BeaversSanjay BhadadaHarry BlairRobert Blank**Elizabeth BradleyMikkel BrentJacques Brown*Lucas BrunBjoern BuehringEllish BurkeDavid B. Burke.布尔*比约恩-布塞Jay J. Cao达娜-卡彭特Alesandra Carriero詹姆斯-卡萨特Naibedya Chattopadhyay陈建良*陈进然Je-Yong Choi克里斯蒂安娜-西普里安Brian C.ClarkMartine Cohen-SolalAdi Cohen**Mary ColeKelsey CollinsFabio Vasconcellos ComimTim CootesSabrina CorbettaNicola CrabtreeApril CraftCarolyn CrandallJames Cray*Laura CreemersSouadDaamouchRafael de MolonSusan DiemNaomi DirckxSinee DisthabanchongPaola Divieti Pajevic*Kate DuchownyEmma DuncanFlorent ElefteriouKlaus EngelkeDaniel EvansPeterPerFabianAlberto Falchetti*Charles FarberVirginia FergusonAníbal FerreiraTrine Elisabeth FinnesAntonella Forlino*Andrea FoxMorten FrostSeiji Fukumoto**Dana GaddyGustavo GarletDamian Genetos**Samuel GhatanCharles GinsbergNeil GittoesDavid GoldhamerCorinna GrasemannMatthew Greenblatt*Jennifer GregoryAnne Grethe JurikYaodong Gu*Scott A..GuelcherAnyonya GunturMelanie Haffner-LuntzerDieter HaffnerMark HamrickSarah Hardcastle****Nan HatchAlberto Hidalgo-BravoKevin HoffsethHironori HojoNilsson HolguinMichael HolickKara Holloway-KewKuo-Chin HuangJulie HughesSteven Ing*Alex IrelandCarlos Isales**M.Kassim JavaidKarl JepsenEijiro JimiFjola Johannesdottir*Mark JohnsonHiroshi KajiLamya KarimKurt KennelHa-Neui Kim*Keunyoung KimFrank Ko**Joyce S.B.KohYoshihiro KomatsuSung Hye KongSusan KrumTakuo KubotaLisa LangsetmoChristine LaryMichael LaurentCarole Le Henaff*Maarit LeinonenWilliam LeslieMichael LevineHuiqi LiMichael T.C..LiangCesar LebanatiEva LiuHuan LiuJulian LuiGuillaume MabilleauHeather MacdonaldJay MagazinerOuti Makitie*KimManskyClaudio MarcocciTakamitsu MaruyamaYuki MatsumuraTakehiko MatsushitaYukiGherardo MazziottiGabriel MbalavieleMichael McClungMeghan McGee-Lawrence**Donal McNallyRobert MeertensDaniela Merlotti*LisaK.MicklesfieldSalvivier*MicklesfieldSalvivier*LisaK.MicklesfieldSalvatore Minisola*Takeshi MiyamotoSharonMoePierre MoffattSubburaman MohanRebecca MoonRoy MorelloKendall Moseley*Katherine MotylChristian MuschitzSandesh NagamaniMark NanesThomas NickolasKeizo NishikawaRobert NissensonJeffry S.NymanMícheál Ó BreasailRalf OheimCatherine OmosuleNoriaki Ono*Wanida OnoBenjamin OsipovMiguel OteroNeil PaloianSerk In ParkEleftherios Paschalis*Erwin PauwsJohn PettiforMarcelo PinheiroLilian Plotkin**IgnacioPortales CastilloSudhaker RaoAlexander RauchFrank RauchMartina RaunerRevit RegevIan ReidR.RevueltaIniestaYumie RheeAmy RibetAlexander RodriguezTim RolvienGenevieve RomanowiczTamara RozentalMishaela RubinEric RushDanielle RuxNithin SKhashayar SakhaeeAmy SatoDominik SaulMitchell SchafflerErica SchellerInez SchoenmakersAnn Schwartz*Peter SchwarzDavid S

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Corneal and Coronary Calcification in Maintenance Hemodialysis: The Face Is No Index to the Heart 维持性血液透析中的角膜和冠状动脉钙化：脸不是心脏的索引

IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM

JBMR Plus

Pub Date : 2023-12-13 DOI: 10.1002/jbm4.10823

Maria Beatriz C. N. Pessoa, Ruth Miyuki Santo, Aline A. de Deus, Eduardo J Duque, Shirley F. Crispilho, Vanda Jorgetti, Maria Aparecida Dalboni, Carlos Eduardo Rochitte, Rosa M. A. Moyses, Rosilene M. Elias

Although the eyes are the main site of metastatic calcification in patients with chronic kidney disease (CKD), corneal and conjunctival calcification (CCC) is poorly evaluated in this population. Whether CCC correlates with coronary artery calcification remains unknown since studies so far have relied on methods with low sensitivity. Our objective was to test the relationship between CCC and coronary calcification based on tomography. This was a cross-sectional study that included patients on maintenance dialysis. Clinical, demographic, and biochemical data (calcium, phosphorus, parathormone, alkaline phosphatase, and 25(OH)-vitamin D) were recorded. Hyperparathyroidism was defined as parathyroid hormone (PTH) > 300 pg/mL. CCC was evaluated by anterior segment optical coherence tomography (AS-OCT), and coronary calcium scores (Agatston method) were assessed by computed tomography. We compared no/mild with moderate/severe CCC. Twenty-nine patients were included (49.6 ± 15.0 years, 62.1% female, on hemodialysis for 5.7 [2.7–9.4] years, 17.2% with diabetes mellitus, 75.9% with hyperparathyroidism). CCC was found in 82.7% of patients, with median scores of 9 (3, 14.5), ranging from 0 to 16. CCC was classified as absent/mild, moderate, and severe in 27.6%, 20.7%, and 51.7%, respectively. Coronary calcification was found in 44.8% of patients, with median scores of 11 (0, 464), varying from 0 and 6456. We found no significant correlation between coronary calcium scores and CCC (r = 0.203, p = 0.282). Hyperphosphatemia was more frequent in patients with moderate/severe CCC than in those with absent/mild CCC. We concluded that CCC was frequent in patients with CKD on dialysis and did not correlate with coronary calcium scores. Hyperphosphatemia appears to contribute to CCC. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

虽然眼睛是慢性肾脏病（CKD）患者转移性钙化的主要部位，但对这一人群的角膜和结膜钙化（CCC）评估却很少。CCC 是否与冠状动脉钙化相关仍是未知数，因为迄今为止的研究都依赖于灵敏度较低的方法。我们的目的是根据断层扫描检测 CCC 与冠状动脉钙化之间的关系。这是一项包括维持性透析患者在内的横断面研究。研究记录了临床、人口统计学和生化数据（钙、磷、副甲状腺激素、碱性磷酸酶和 25(OH)-vitamin D）。甲状旁腺功能亢进的定义是甲状旁腺激素（PTH）超过 300 pg/mL。CCC通过前段光学相干断层扫描（AS-OCT）进行评估，冠状动脉钙化评分（Agatston法）通过计算机断层扫描进行评估。我们将无/轻度 CCC 与中度/重度 CCC 进行了比较。共纳入 29 名患者（49.6 ± 15.0 岁，62.1% 为女性，血液透析 5.7 [2.7-9.4] 年，17.2% 患有糖尿病，75.9% 患有甲状旁腺功能亢进）。82.7%的患者发现了 CCC，中位数为 9（3，14.5）分，范围从 0 到 16。分别有27.6%、20.7%和51.7%的患者将CCC分为无/轻度、中度和重度。44.8%的患者发现冠状动脉钙化，中位数为 11（0，464）分，从 0 到 6456 分不等。我们发现冠状动脉钙化评分与 CCC 之间无明显相关性（r = 0.203，p = 0.282）。中度/重度 CCC 患者的高磷血症发生率高于无/轻度 CCC 患者。我们的结论是，透析治疗的慢性肾脏病患者中经常出现 CCC，而且与冠状动脉钙化评分无关。高磷血症似乎是导致 CCC 的原因之一。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC 代表美国骨与矿物质研究学会出版。

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引用次数: 0