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Fabric–elasticity relationships of femoral head trabecular bone are similar in Type 2 diabetes and non-diabetic individuals 2型糖尿病和非糖尿病患者股骨头小梁的纤维弹性关系相似
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 Epub Date: 2025-10-29 DOI: 10.1016/j.bonr.2025.101884
Mathieu Simon , Sasidhar Uppuganti , Jeffry S. Nyman , Philippe Zysset
<div><div>Type 2 diabetes (T2D) is a chronic disease leading to an elevated glucose level in the blood and increased fracture risk. Because T2D individuals tend to have normal to higher areal bone mineral density (aBMD) than healthy individuals, their fracture risk is often underestimated. As an alternative, high-resolution peripheral quantitative computed tomography (HR-pQCT) is an attractive tool to investigate bone morphology in vivo and estimate fracture risk. Based on HR-pQCT scans, bone strength can be estimated using micro finite element (<span><math><mi>μ</mi></math></span>FE) analysis or homogenized finite element (hFE) analysis. While <span><math><mi>μ</mi></math></span>FE is computationally expensive, hFE provides an accurate estimation of bone mechanical properties within reasonable efforts. However, the hFE scheme is based on relationships between the local fabric (anisotropy) and elasticity. These relationships have been shown to hold for healthy controls as well as in the case of osteogenesis imperfecta. Nevertheless, whether these relationships are also valid for T2D-diagnosed patients remains unclear. Therefore, the present work aims to compare fabric–elasticity relationships between T2D and non-diabetic controls.</div><div>The present study collected 56 trabecular bone cores from the femoral head of 28 T2D and 28 control donors. These cadaveric samples were scanned in a micro-CT system at an isotropic 14.8 <span><math><mi>μ</mi></math></span>m voxel size. Three cubic regions of interest (ROIs) were selected in each scan. The resolution of these ROIs was coarsened by a factor of 4, mimicking clinical HR-pQCT resolution, and the ROIs were subsequently segmented. Standard morphometric parameters were computed from the segmented ROIs using medtool (v4.8; Dr. Pahr Ingenieurs e.U., Pfaffstätten, Austria). Additionally, their fabric tensor and their apparent stiffness tensors were computed. The ROIs were compared between T2D and control regarding their morphometric and mechanical properties. Finally, ROIs were matched between T2D and control for bone volume fraction (<span><math><mi>ρ</mi></math></span>) and degree of anisotropy (DA). The matched dataset allowed the comparison of fabric–elasticity relationships between T2D and control samples.</div><div>No significant difference was observed between T2D and control samples, both regarding their morphology and their mechanical properties. Specifically, fabric–elasticity relationships were shown to hold for both the control and the T2D groups. A comparison of the resulting exponents related to <span><math><mi>ρ</mi></math></span> and DA has highlighted different trends but no important difference between T2D and control samples.</div><div>In conclusion, trabecular bone architecture was similar between T2D and non-T2D donors. Additionally, fabric–elasticity relationships, i.e. morphology-mechanical relationships, are also similar between donors with and without diabetes. Accordingly, HR-p
2型糖尿病(T2D)是一种导致血液中葡萄糖水平升高和骨折风险增加的慢性疾病。由于T2D患者的面骨矿物质密度(aBMD)往往高于健康人群,因此他们的骨折风险往往被低估。作为替代方案,高分辨率周边定量计算机断层扫描(HR-pQCT)是一种有吸引力的工具,用于研究体内骨形态和估计骨折风险。基于HR-pQCT扫描结果,可采用微有限元(μFE)分析或均质有限元(hFE)分析估算骨强度。虽然μFE在计算上是昂贵的,但hFE在合理的努力下提供了骨力学性能的准确估计。然而,hFE方案是基于局部结构(各向异性)和弹性之间的关系。这些关系已被证明适用于健康对照以及成骨不全症。然而,这些关系是否也适用于t2d诊断患者仍不清楚。因此,本研究旨在比较T2D和非糖尿病对照之间的织物弹性关系。本研究从28例T2D供体和28例对照供体的股骨头中收集了56个骨小梁核心。这些尸体样品在微ct系统中以各向同性14.8 μm体素尺寸进行扫描。在每次扫描中选择三个立方感兴趣区域(roi)。这些roi的分辨率被粗化4倍,模仿临床HR-pQCT分辨率,随后对roi进行分割。使用medtool (v4.8; Dr. Pahr Ingenieurs e.U, Pfaffstätten,奥地利)从分割的roi中计算标准形态计量参数。此外,还计算了它们的织物张量和表观刚度张量。比较了T2D和对照组在形态计量学和力学性能方面的roi。最后,在骨体积分数(ρ)和各向异性程度(DA)方面,将T2D与对照组的roi进行匹配。匹配的数据集允许比较T2D和对照样本之间的织物弹性关系。在T2D和对照样品之间,无论是形貌还是力学性能都没有观察到显著差异。具体来说,织物弹性关系被证明对对照组和T2D组都有效。与ρ和DA相关的结果指数的比较突出了不同的趋势,但在T2D和控制样本之间没有重要差异。总之,T2D和非T2D供体的骨小梁结构相似。此外,织物-弹性关系,即形态-力学关系,在有和没有糖尿病的供体之间也相似。因此,基于hr - pqct的hFE分析也可用于估计T2D患者的骨力学特性和评估其骨折风险。
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引用次数: 0
Nanostructural changes in bone quality in a mouse model of chronic kidney disease and treatment with calcitonin 慢性肾脏疾病小鼠模型骨质量的纳米结构变化及降钙素治疗
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 Epub Date: 2025-10-01 DOI: 10.1016/j.bonr.2025.101880
E. Montagnino , W. Bush , J. Bustamante , W. Bandara , P. Jalaie , M.R. Allen , J.M. Wallace , T. Siegmund , R.K. Surowiec , J.A. Howarter
Mineral imbalances in the body from chronic kidney disease can impact bone turnover and cause cortical bone loss. Synthetic salmon calcitonin is an FDA-approved treatment for bone fragility observed in diseases such as osteoporosis, and clinical trials have demonstrated a reduction in fractures compared to untreated individuals. This study documents the effects of calcitonin on cortical bone using an in vivo mouse model of chronic kidney disease. Serum BUN and PTH are reported. Calcitonin was found to impact at a dose of 50/IU/kg/day five times a week for five weeks. MicroCT was used to evaluate bone quantity measures, such as cortical porosity, thickness, bone area, and long bone structural geometric parameters. It was found that porosity, thickness, and bone geometry are affected by disease, but not by treatment at the specified regime. Small and wide-angle x-ray scattering (SAXS and WAXS) was used to obtain the nanostructure of the mineral-collagen-water composite, including mineral dimensions, D-periodicity and collagen spacing. Data from thermogravimetric analysis (TgA) were used to quantify wt.% of the mineral, collagen, and bound water of each sample. Chronic kidney disease was found to decrease collagen spacing to increase mineral weight fractions, and to reduce loosely bound water. There were no changes from chronic kidney disease on the D-Periodicity. Treatment increased the weight percent of collagen, with no effect on other bone quality parameters.
慢性肾脏疾病引起的体内矿物质失衡会影响骨转换并导致皮质骨丢失。合成鲑鱼降钙素是一种fda批准的治疗骨质疏松症等疾病中观察到的骨质疏松的药物,临床试验表明,与未经治疗的个体相比,服用三文鱼降钙素可以减少骨折的发生。本研究利用慢性肾脏疾病小鼠体内模型记录了降钙素对皮质骨的影响。报告血清BUN和甲状旁腺素。降钙素在50/IU/kg/天的剂量下被发现有影响,每周5次,持续5周。MicroCT用于评估骨量测量,如皮质孔隙度、厚度、骨面积和长骨结构几何参数。发现孔隙度、厚度和骨几何形状受疾病影响,但不受特定治疗方案的影响。利用小角和广角x射线散射(SAXS和WAXS)获得了矿物-胶原-水复合材料的纳米结构,包括矿物尺寸、d -周期性和胶原间距。热重分析(TgA)的数据用于量化每个样品中wt.%的矿物质、胶原蛋白和结合水。慢性肾脏疾病被发现减少胶原蛋白间距,增加矿物质重量分数,并减少松散结合水。慢性肾脏疾病在d -周期上没有变化。治疗增加了胶原蛋白的重量百分比,对其他骨质量参数没有影响。
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引用次数: 0
Cyclin-dependent kinase inhibitor-1 deficiency enhances bone destruction in a mouse model of arthritis 细胞周期蛋白依赖性激酶抑制剂-1缺乏增强关节炎小鼠模型的骨破坏
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 DOI: 10.1016/j.bonr.2025.101892
Kensuke Wada , Shinya Hayashi , Yuma Onoi , Shotaro Tachibana , Yoshihito Suda , Akira Saito , Takuma Maeda , Shotaro Araki , Kohei Motono , Tomoyuki Kamenaga , Masanori Tsubosaka , Yuichi Kuroda , Naoki Nakano , Tomoyuki Matsumoto , Ryosuke Kuroda
Rheumatoid arthritis (RA) causes bone destruction by activating inflammatory cytokines and osteoclasts. Cyclin-dependent kinase inhibitor 1 (p21), a cell cycle regulator, may influence this process; however, its role remains unclear. Therefore, we investigated the effect and potential mechanisms of p21 deficiency in bone loss in a mouse model of arthritis. Collagen antibody-induced arthritis (CAIA) was established in p21 knockout (p21−/−) and wild-type mice. Bone destruction was analyzed using histology, micro-computed tomography, and bone strength testing; osteoclast formation and activity were evaluated using tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry for cathepsin K. The expression of inflammatory cytokines and osteoclast-related genes was examined using immunohistochemistry and real-time polymerase chain reaction, respectively. p21/ mice exhibited greater bone destruction and lower bone strength than wild-type mice. Additionally, TRAP and cathepsin K staining revealed significantly higher osteoclast count in p21/ mice. Interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), and phosphorylated signal transducer and activator of transcription 3 (STAT3) levels were considerably higher in bone tissues of p21/ mice than in those of wild-type mice. In vitro osteoclast differentiation in bone marrow macrophages (BMMs) was examined after IL-6 stimulation; osteoclast differentiation and osteoclast marker gene expression were significantly enhanced in p21−/− BMMs. Western blotting confirmed increased STAT3 phosphorylation in p21−/− BMMs; IL-6 treatment further amplified osteoclastogenesis in p21−/− BMMs. In conclusion, p21 deficiency exacerbates bone destruction in arthritis by promoting osteoclast differentiation and inflammatory cytokine expression via the IL-6/STAT3 pathway. Targeting p21 may offer therapeutic potential for preventing arthritis-related bone loss, such as in RA.
类风湿关节炎(RA)通过激活炎症细胞因子和破骨细胞导致骨破坏。细胞周期蛋白依赖性激酶抑制剂1 (p21),一种细胞周期调节剂,可能影响这一过程;然而,它的作用仍不清楚。因此,我们在关节炎小鼠模型中研究了p21缺乏对骨质流失的影响及其潜在机制。在p21敲除(p21−/−)和野生型小鼠中建立胶原抗体诱导关节炎(CAIA)。采用组织学、显微计算机断层扫描和骨强度测试分析骨破坏情况;采用抗酒石酸酸性磷酸酶(TRAP)染色和组织蛋白酶k的免疫组化检测破骨细胞的形成和活性。分别采用免疫组化和实时聚合酶链反应检测炎症细胞因子和破骨细胞相关基因的表达。与野生型小鼠相比,P21−/−小鼠表现出更大的骨破坏和更低的骨强度。此外,TRAP和组织蛋白酶K染色显示p21−/−小鼠的破骨细胞计数显著增加。与野生型小鼠相比,p21−/−小鼠骨组织中白介素(IL)-6、IL-1β、肿瘤坏死因子-α (TNF-α)和磷酸化信号换能器和转录激活因子3 (STAT3)水平明显升高。IL-6刺激后观察骨髓巨噬细胞(BMMs)体外破骨细胞分化;破骨细胞分化和破骨细胞标记基因表达在p21−/−BMMs中显著增强。Western blotting证实p21−/−BMMs中STAT3磷酸化增加;IL-6治疗进一步放大了p21−/−BMMs的破骨细胞生成。综上所述,p21缺乏通过IL-6/STAT3通路促进破骨细胞分化和炎症细胞因子表达,从而加剧关节炎的骨破坏。靶向p21可能为预防关节炎相关的骨质流失提供治疗潜力,例如在RA中。
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引用次数: 0
A novel workflow for 3D imaging and spatial analysis of nerves in bone 骨神经三维成像和空间分析的新工作流程
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 Epub Date: 2025-10-02 DOI: 10.1016/j.bonr.2025.101881
Allison L. Horenberg , Eric Z. Zeng , Yunke Ren , Tanishk Sinha , Emith Uyanwatte , Melia Matthews , Erica L. Scheller , Karl J. Lewis , Arvind P. Pathak , Warren L. Grayson
Peripheral sensory and sympathetic nerves innervating bony tissues are of interest for their role in modulating bone function and responding to physiologic stimuli. However, due to their filamentous structure and small diameter, peripheral nerves are difficult to visualize and characterize in dense tissues such as bone. Recent advances in imaging have resulted in novel techniques to reconstruct the 3D bone microenvironment following fluorescent staining, using methods such as whole-mount immunostaining, tissue clearing, and lightsheet microscopy (LSM). While these methods have significantly improved visualization of peripheral nerves within the bony skeleton, current practices in skeletal nerve segmentation rely on manual tracing methods that are both subjective and time consuming. Further, due to excess background signal and moderate off-target staining of skeletal nerves, traditional methods for nerve segmentation remain inadequate for effective quantification. Here, we describe a methods-focused workflow for 3D imaging and spatial analysis of nerves in bone that consists of combining LSM with nerve segmentation using the Ilastik® open-source software. First, LSM was used to acquire high-resolution 3D images of nerves in uninjured and injured murine calvaria. Next, we employed Ilastik® to generate accurate segmentations of peripheral nerves in bone. This approach reduced the need for manual segmentation and overcame the limitations of conventional segmentation methods. We then demonstrated the utility of this workflow as a broadly applicable tool, by performing Ilastik®-based segmentation for three distinct skeletal bone contexts (i.e. use cases) with varied bone samples, tissue clearing, processing protocols, inflammatory states, and imaging modalities. Collectively, this workflow enabled the characterization of spatial nerve patterning in bone and has the potential to provide novel insights into spatially regulated phenomena in bone homeostasis, injury, and disease.
支配骨组织的外周感觉和交感神经因其在调节骨功能和对生理刺激的反应中的作用而受到关注。然而,由于其丝状结构和小直径,周围神经在骨等致密组织中难以可视化和表征。成像技术的最新进展产生了新的技术,可以在荧光染色后重建三维骨微环境,使用的方法包括全贴装免疫染色、组织清除和光片显微镜(LSM)。虽然这些方法显著改善了骨骼内周围神经的可视化,但目前骨骼神经分割的实践依赖于人工追踪方法,这种方法既主观又耗时。此外,由于骨骼神经的背景信号过多和中度脱靶染色,传统的神经分割方法仍不足以有效量化。在这里,我们描述了一个以方法为中心的工作流程,用于骨中神经的3D成像和空间分析,其中包括使用Ilastik®开源软件将LSM与神经分割相结合。首先,利用LSM获取未损伤和损伤小鼠颅骨神经的高分辨率三维图像。接下来,我们使用Ilastik®生成骨内周围神经的准确分割。该方法减少了人工分割的需要,克服了传统分割方法的局限性。然后,我们通过对具有不同骨样本、组织清理、处理方案、炎症状态和成像方式的三种不同骨骼环境(即用例)执行基于Ilastik®的分割,展示了该工作流程作为广泛适用工具的实用性。总的来说,该工作流程能够表征骨中的空间神经模式,并有可能为骨稳态、损伤和疾病中的空间调节现象提供新的见解。
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引用次数: 0
Scavenging methylglyoxal improves bone quality and defect healing in diabetic mice 清除甲基乙二醛改善糖尿病小鼠骨质量和缺陷愈合
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 Epub Date: 2025-10-29 DOI: 10.1016/j.bonr.2025.101883
Toshifumi Hikichi , Kumi Kimura , Seiichi Munesue , Yu Oshima , Ai Harashima , Tomo Hamada , Kanu Shimokawa , Yuki Fushitani , Hisanori Goto , Hiroyuki Tsuchiya , Satoru Demura , Hidenori Matsubara , Yasuhiko Yamamoto
Hyperglycemia in diabetes leads to the formation of methylglyoxal (MG) and accumulation of advanced glycation end-products (AGEs). We previously reported that exogenous MG exposure deteriorated osteoblastic differentiation in vitro and diabetic mice showed delayed bone defect healing along with elevated MG-derived AGE levels. However, whether endogenously formed MG is involved in impaired bone repair and remodeling in diabetes remains unclear. In this study, we investigated the effects of hyperglycemia-induced MG formation on bone quality and defect healing in mice. Using a synthetic MG probe [Ir(ppy)2(DA-phen)], we found that endogenous MG formation deteriorated osteoblastic and osteoclastic differentiation under hyperglycemic conditions in cultured cells. In the bone defect site of streptozotocin (STZ)-induced diabetic mice, along with impaired defect healing, we observed elevated endogenous MG levels and downregulation of alkaline phosphatase (ALP) compared with that in non-diabetic control mice; however, these alterations were alleviated by managing blood glucose levels through insulin supplementation. Furthermore, treatment with pyridoxamine (PM), an MG scavenger, ameliorated these impairments by suppressing MG elevation and upregulating the expression of osteocalcin, osteoprotegerin, and osteoclast-associated receptor genes without improving the diabetic status. These findings suggest that endogenously formed MG is detrimental to hyperglycemia-related delayed bone defect healing in type 1 diabetes mellitus (T1DM). Collectively, this study suggests that MG scavenging by PM and suppression of MG formation by glycemic control are potential therapeutic strategies for T1DM-associated bone disorders.
糖尿病的高血糖导致甲基乙二醛(MG)的形成和晚期糖基化终产物(AGEs)的积累。我们之前报道过外源性MG暴露会使体外成骨细胞分化恶化,糖尿病小鼠的骨缺损愈合延迟,同时MG源性AGE水平升高。然而,内源性形成的MG是否参与糖尿病的骨修复和重塑受损尚不清楚。在本研究中,我们研究了高血糖诱导的MG形成对小鼠骨质量和缺损愈合的影响。使用合成的MG探针[Ir(ppy)2(DA-phen)],我们发现内源性MG的形成在高血糖条件下恶化了培养细胞的成骨细胞和破骨细胞的分化。在链脲佐菌(STZ)诱导的糖尿病小鼠骨缺损部位,与非糖尿病对照组相比,我们观察到内源性MG水平升高,碱性磷酸酶(ALP)下调;然而,通过补充胰岛素来控制血糖水平可以减轻这些变化。此外,吡哆沙明(PM)治疗,一种MG清除剂,通过抑制MG升高和上调骨钙素、骨保护素和破骨细胞相关受体基因的表达来改善这些损伤,而不改善糖尿病状态。这些发现表明,内源性形成的MG对1型糖尿病(T1DM)患者高血糖相关的延迟骨缺损愈合是有害的。总之,本研究表明,通过PM清除MG和通过血糖控制抑制MG的形成是治疗t1dm相关骨骼疾病的潜在策略。
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引用次数: 0
Increased fatty acid availability improves the osteo-anabolic effects of intermittent parathyroid hormone (iPTH) in murine models 增加脂肪酸可用性改善间歇性甲状旁腺激素(iPTH)在小鼠模型中的骨合成代谢作用
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 Epub Date: 2025-11-09 DOI: 10.1016/j.bonr.2025.101887
Santosh Thapa , Jake Newberry , S.V.V.S. Ravi Mangu , Ron C.M. Helderman , Ananya Nandy , Cameron Fawcett , Sasidhar Uppuganti , Jeffry S. Nyman , Elizabeth Rendina-Ruedy
Osteoporosis is a major public health problem which results in reduced bone mineral density (BMD) and increased fracture risk. Osteoporosis-related fractures often lead to multiple comorbidities which can significantly reduce longevity and diminish one's quality of life. While anabolic agents that increase bone formation, such as parathyroid hormone (PTH), have aided in the management of osteoporosis, patients still experience adverse side-effects along with variations in therapeutic response. Therefore, continued development of refined therapeutic interventions as well as improving efficacy is necessary. Relative to this, the current experiments report on the ability to harness PTH's impact to modulate osteoblast bioenergetic capacity to promote bone formation by supplying fatty acid substrates to meet this energetic demand. To accomplish this, mice were fed a moderately ‘high’ fat diet (2.5×) or control fat, as to not induce metabolic perturbations, while treating with or without PTH for 4 weeks. This dietary regimen resulted in improved bone parameters in mice fed the high fat diet compared to control diet. To directly test the contribution of increased exogenous fatty acid substrates during PTH treatment, we next introduced oleic acid simultaneous to PTH treatment for 4 weeks, and again showed improved skeletal parameters compared to the vehicle-control treated mice. These data support previous publications that demonstrate the osteoanabolic responsiveness of osteoblasts to PTH requires fatty acid substrates. These data further expand on these findings, by providing evidence that PTH efficacy can be improved by supplying exogenous fatty acid substrates, either by dietary or direct interventions.
骨质疏松症是导致骨密度降低和骨折风险增加的主要公共卫生问题。骨质疏松相关骨折通常会导致多种合并症,这些合并症会显著降低患者的寿命和生活质量。虽然增加骨形成的合成代谢药物,如甲状旁腺激素(PTH),有助于骨质疏松症的治疗,但患者仍然会经历不良的副作用以及治疗反应的变化。因此,继续发展完善的治疗干预措施以及提高疗效是必要的。与此相关,目前的实验报道了利用甲状旁腺激素的影响来调节成骨细胞的生物能量能力,通过提供脂肪酸底物来满足这种能量需求,从而促进骨形成的能力。为了实现这一目标,小鼠被喂食中度“高”脂肪饮食(2.5倍)或控制脂肪,以不引起代谢紊乱,同时用或不用甲状旁腺激素治疗4周。与对照组相比,这种饮食方案改善了喂食高脂肪饮食的小鼠的骨骼参数。为了直接测试在PTH治疗期间外源性脂肪酸底物增加的贡献,我们接下来在PTH治疗的同时引入油酸4周,与对照组相比,再次显示骨骼参数得到改善。这些数据支持先前的出版物,证明成骨细胞对甲状旁腺激素的骨合成代谢反应需要脂肪酸底物。这些数据进一步扩展了这些发现,通过提供证据表明,通过饮食或直接干预,提供外源性脂肪酸底物可以改善甲状旁腺激素的功效。
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引用次数: 0
The effects of geranylgeranyl diphosphate synthase inhibitor treatment on osteoblast biology and application in a conditioned media model of myeloma bone disease 香叶香叶二磷酸合成酶抑制剂对成骨细胞生物学的影响及其在骨髓瘤骨病条件介质模型中的应用
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 Epub Date: 2025-09-03 DOI: 10.1016/j.bonr.2025.101874
Molly E. Muehlebach , Sarah A. Holstein
Myeloma bone disease (MBD) is characterized by tumor-induced osteoclast activation with concomitant suppression of osteoblast activity. Nitrogen bisphosphonates (NBPs), including zoledronic acid (ZA), are a mainstay of MBD treatment, due to their anti-osteoclastic effects secondary to high bone affinity and indirect disruption of protein geranylgeranylation through inhibition of farnesyl diphosphate synthase. The development of geranylgeranyl diphosphate synthase (GGDPS) inhibitors (GGSIs) represents a more selective means of targeting geranylgeranylation. The GGSI RAM2061 has direct anti-myeloma activity in vitro and in vivo, achieves both systemic and skeletal distribution, and has anti-osteoclastic activity. However, the effects of this novel therapy on osteoblast activity or in a setting that recapitulates the MBD milieu have yet to be explored. Exposure to RAM2061 or ZA during MC3T3-E1 differentiation resulted in impairment in osteoblast function, including alkaline phosphatase and mineralization activity, however minimal effects were observed in differentiated MC3T3-E1 cells that were subsequently exposed to drug. To evaluate the impact of RAM2061 on osteoblast or osteoclast activity under MBD-like conditions, JJN3 myeloma cell conditioned media (CM) was collected and added to bone cell cultures in order to simulate osteoclast-activating or osteoblast-inhibitory MBD microenvironments. These studies determined that RAM2061 maintains anti-resorptive effects and osteoblast inhibitory effects in undifferentiated precursors while in the presence of JJN3 CM. However, no appreciable effects were detected in osteoblasts exposed to drug post-differentiation. Overall, these studies contribute to the mechanistic understanding of NBP and GGSI effects in the bone and provide support for the continued investigation of GGSIs in MBD.
骨髓瘤骨病(MBD)的特点是肿瘤诱导的破骨细胞激活并伴随成骨细胞活性抑制。双膦酸氮(NBPs),包括唑来膦酸(ZA),是MBD治疗的主要药物,因为它们具有抗破骨作用,继发于高骨亲和力和通过抑制法尼基二磷酸合成酶间接破坏蛋白香叶酰化。香叶酰香叶酰二磷酸合成酶(GGDPS)抑制剂(GGSIs)的开发代表了一种更具选择性的靶向香叶酰化的方法。GGSI RAM2061在体外和体内均具有直接的抗骨髓瘤活性,实现全身分布和骨骼分布,具有抗破骨活性。然而,这种新疗法对成骨细胞活性的影响或在重现MBD环境的环境中仍有待探索。在MC3T3-E1分化过程中暴露于RAM2061或ZA会导致成骨细胞功能受损,包括碱性磷酸酶和矿化活性,但对随后暴露于药物的分化MC3T3-E1细胞的影响很小。为了评估RAM2061对MBD样条件下成骨细胞或破骨细胞活性的影响,收集JJN3骨髓瘤细胞条件培养基(CM)并将其添加到骨细胞培养中,以模拟破骨细胞激活或成骨细胞抑制MBD微环境。这些研究表明,当存在JJN3 CM时,RAM2061在未分化的前体中保持抗吸收作用和成骨细胞抑制作用。然而,在暴露于药物分化后的成骨细胞中没有发现明显的影响。总的来说,这些研究有助于了解NBP和GGSI在骨中的作用机制,并为GGSI在MBD中的持续研究提供支持。
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引用次数: 0
High-fat diet induced obesity and anti-activin receptor antibody: Effects on bone properties in mice 高脂饮食诱导肥胖和抗活动性受体抗体:对小鼠骨骼特性的影响
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-12-01 Epub Date: 2025-09-19 DOI: 10.1016/j.bonr.2025.101878
Frederik Duch Bromer , Andreas Lodberg , Lykke Sylow , Michala Carlsson , Christian Brix Folsted Andersen , Jesper Skovhus Thomsen , Annemarie Brüel

Aim

Weight-loss therapy often results in an unintended loss of muscle and bone mass. Inhibitors of the activin receptor signaling pathway, such as bimagrumab, an anti-activin receptor antibody (αActRIIA/IIB ab), are under investigation to counteract weight-loss induced muscle loss, but their skeletal effects in obesity remain unclear. This study investigates αActRIIA/IIB ab on bone in mice exposed to a high-fat diet (HFD) model of obesity or standard chow.

Materials and methods

Male C57BL/6 J mice were stratified into four groups (n = 10/group, standard chow or HFD for 10 weeks ± αActRIIA/IIB ab). αActRIIA/IIB ab (10 mg/kg) was administered twice weekly during the final three weeks. The femur and vertebral body were assessed using DEXA, μCT, mechanical testing, and histomorphometry.

Results

HFD did not affect bone density, microstructure, or strength but reduced histological bone formation markers. In standard chow mice, αActRIIA/IIB ab increased trabecular bone volume fraction (BV/TV) and volumetric bone mineral density (vBMD) by 36 %. In HFD mice, the effect of αActRIIA/IIB ab was less pronounced but still increased BV/TV (+16 %) and vBMD (+13 %). For cortical bone, μCT parameters remained largely unaffected by αActRIIA/IIB ab, while the treatment increased periosteal mineralizing bone surfaces in standard chow mice (+217 %), but not in HFD mice.

Conclusions

αActRIIA/IIB ab enhanced trabecular bone properties in standard chow-fed mice, but its anabolic effects were blunted in HFD-fed mice. Furthermore, αActRIIA/IIB ab improved cortical histological bone formation markers, while morphology remained unaffected, suggesting a site- or time-specific difference. Thus, αActRIIA/IIB ab holds potential for mitigating weight-loss-associated bone deterioration.
减肥疗法通常会导致肌肉和骨量的意外减少。激活素受体信号通路抑制剂,如bimagrumab,一种抗激活素受体抗体(αActRIIA/IIB ab),正在研究中,以抵消减肥引起的肌肉损失,但其对肥胖的骨骼影响尚不清楚。本研究研究了αActRIIA/IIB抗体在高脂肪饮食(HFD)肥胖模型或标准食物小鼠骨骼中的作用。材料与方法将C57BL/ 6j小鼠分为4组(n = 10只/组,标准饲料或HFD, 10周±αActRIIA/IIB ab)。最后3周每周2次给药αActRIIA/IIB ab (10 mg/kg)。采用DEXA、μCT、力学测试和组织形态学对股骨和椎体进行评估。结果shfd不影响骨密度、显微结构和强度,但降低了骨组织形成标志物。αActRIIA/IIB ab可使标准鼠小梁骨体积分数(BV/TV)和体积骨密度(vBMD)提高36%。在HFD小鼠中,αActRIIA/IIB抗体的作用不太明显,但仍能提高BV/TV(+ 16%)和vBMD(+ 13%)。对于皮质骨,μCT参数基本不受αActRIIA/IIB ab的影响,而在标准小鼠中,处理增加了骨膜矿化骨表面(+ 217%),但在HFD小鼠中没有。结论α actriia /IIB ab增强了标准周食小鼠的骨小梁性能,但对hfd小鼠的合成代谢作用减弱。此外,αActRIIA/IIB ab改善了皮质组织学骨形成标志物,而形态学未受影响,表明存在位点或时间特异性差异。因此,αActRIIA/IIB ab具有减轻体重减轻相关的骨质恶化的潜力。
{"title":"High-fat diet induced obesity and anti-activin receptor antibody: Effects on bone properties in mice","authors":"Frederik Duch Bromer ,&nbsp;Andreas Lodberg ,&nbsp;Lykke Sylow ,&nbsp;Michala Carlsson ,&nbsp;Christian Brix Folsted Andersen ,&nbsp;Jesper Skovhus Thomsen ,&nbsp;Annemarie Brüel","doi":"10.1016/j.bonr.2025.101878","DOIUrl":"10.1016/j.bonr.2025.101878","url":null,"abstract":"<div><h3>Aim</h3><div>Weight-loss therapy often results in an unintended loss of muscle and bone mass. Inhibitors of the activin receptor signaling pathway, such as bimagrumab, an anti-activin receptor antibody (αActRIIA/IIB ab), are under investigation to counteract weight-loss induced muscle loss, but their skeletal effects in obesity remain unclear. This study investigates αActRIIA/IIB ab on bone in mice exposed to a high-fat diet (HFD) model of obesity or standard chow.</div></div><div><h3>Materials and methods</h3><div>Male C57BL/6 J mice were stratified into four groups (<em>n</em> = 10/group, standard chow or HFD for 10 weeks ± αActRIIA/IIB ab). αActRIIA/IIB ab (10 mg/kg) was administered twice weekly during the final three weeks. The femur and vertebral body were assessed using DEXA, μCT, mechanical testing, and histomorphometry.</div></div><div><h3>Results</h3><div>HFD did not affect bone density, microstructure, or strength but reduced histological bone formation markers. In standard chow mice, αActRIIA/IIB ab increased trabecular bone volume fraction (BV/TV) and volumetric bone mineral density (vBMD) by 36 %. In HFD mice, the effect of αActRIIA/IIB ab was less pronounced but still increased BV/TV (+16 %) and vBMD (+13 %). For cortical bone, μCT parameters remained largely unaffected by αActRIIA/IIB ab, while the treatment increased periosteal mineralizing bone surfaces in standard chow mice (+217 %), but not in HFD mice.</div></div><div><h3>Conclusions</h3><div>αActRIIA/IIB ab enhanced trabecular bone properties in standard chow-fed mice, but its anabolic effects were blunted in HFD-fed mice. Furthermore, αActRIIA/IIB ab improved cortical histological bone formation markers, while morphology remained unaffected, suggesting a site- or time-specific difference. Thus, αActRIIA/IIB ab holds potential for mitigating weight-loss-associated bone deterioration.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101878"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118986","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
Corrigendum to “Dose-response effects of alcohol on biochemical markers of bone turnover in non-human primates: Effects of species, sex and age of onset of drinking” [Bone Rep. 16 (2021) 101159] “酒精对非人类灵长类动物骨转换生化标志物的剂量-反应效应:物种、性别和饮酒年龄的影响”的勘误表[bone代表16 (2021)101159]
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-01 Epub Date: 2025-08-07 DOI: 10.1016/j.bonr.2025.101868
M.L. Benton , V.A. Jimenez , N. Newman , S.W. Gonzales , K.A. Grant , R.T. Turner , U.T. Iwaniec , E.J. Baker
{"title":"Corrigendum to “Dose-response effects of alcohol on biochemical markers of bone turnover in non-human primates: Effects of species, sex and age of onset of drinking” [Bone Rep. 16 (2021) 101159]","authors":"M.L. Benton ,&nbsp;V.A. Jimenez ,&nbsp;N. Newman ,&nbsp;S.W. Gonzales ,&nbsp;K.A. Grant ,&nbsp;R.T. Turner ,&nbsp;U.T. Iwaniec ,&nbsp;E.J. Baker","doi":"10.1016/j.bonr.2025.101868","DOIUrl":"10.1016/j.bonr.2025.101868","url":null,"abstract":"","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101868"},"PeriodicalIF":2.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018721","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
Effects of 650 nm laser acupuncture on cartilage, bone, and skeletal muscle in osteoarthritis 650nm激光针刺对骨关节炎软骨、骨和骨骼肌的影响
IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-01 Epub Date: 2025-07-31 DOI: 10.1016/j.bonr.2025.101864
Seung-Ho Seo , Sang-Mi Kang , Yang-Hee You , Chang-Su Na
This study evaluated the therapeutic effects of 650 nm laser acupuncture at 10 mW and 20 mW in a monosodium iodoacetate (MIA) induced osteoarthritis (OA) rat model. OA was induced by intra-articular injection of MIA, and laser acupuncture was applied to GB34 and GB39 twice weekly for four weeks. Cartilage preservation was assessed by Safranin-O staining, pain by hind paw weight distribution, bone structure by micro-CT analysis of bone volume fraction, trabecular volume, and cortical thickness, and muscle condition by histology and wet weight of the gastrocnemius and quadriceps. Both laser treatments reduced cartilage degeneration and improved weight-bearing. The 10 mW group showed greater improvements than the 20 mW group, including higher proteoglycan content, better bone structural parameters, and greater muscle mass. These results indicate that 10 mW laser acupuncture is more effective than 20 mW in reducing joint damage and preserving musculoskeletal tissue. The findings support the use of low-power laser acupuncture as a non-invasive treatment for OA. The study also shows that higher laser power does not necessarily lead to better outcomes, highlighting the need for appropriate dose selection. Further studies are needed to assess long-term effects and investigate underlying mechanisms.
研究了10 mW和20 mW 650 nm激光针刺对碘乙酸钠(MIA)诱导的骨关节炎(OA)大鼠模型的治疗作用。采用MIA关节内注射诱导OA,激光针刺GB34、GB39,每周2次,连续4周。采用Safranin-O染色评估软骨保存情况,采用后爪重量分布评估疼痛情况,采用显微ct分析骨体积分数、骨小梁体积和骨皮质厚度评估骨结构,采用腓肠肌和股四头肌的组织学和湿重评估肌肉状况。两种激光治疗都能减少软骨变性并改善负重。与20 mW组相比,10 mW组表现出更大的改善,包括更高的蛋白聚糖含量、更好的骨结构参数和更大的肌肉质量。这些结果表明,10mw激光针刺在减轻关节损伤和保护肌肉骨骼组织方面比20mw更有效。研究结果支持使用低功率激光针灸作为OA的非侵入性治疗。该研究还表明,更高的激光功率不一定会带来更好的结果,强调了适当剂量选择的必要性。需要进一步的研究来评估长期影响和调查潜在的机制。
{"title":"Effects of 650 nm laser acupuncture on cartilage, bone, and skeletal muscle in osteoarthritis","authors":"Seung-Ho Seo ,&nbsp;Sang-Mi Kang ,&nbsp;Yang-Hee You ,&nbsp;Chang-Su Na","doi":"10.1016/j.bonr.2025.101864","DOIUrl":"10.1016/j.bonr.2025.101864","url":null,"abstract":"<div><div>This study evaluated the therapeutic effects of 650 nm laser acupuncture at 10 mW and 20 mW in a monosodium iodoacetate (MIA) induced osteoarthritis (OA) rat model. OA was induced by intra-articular injection of MIA, and laser acupuncture was applied to GB34 and GB39 twice weekly for four weeks. Cartilage preservation was assessed by Safranin-O staining, pain by hind paw weight distribution, bone structure by micro-CT analysis of bone volume fraction, trabecular volume, and cortical thickness, and muscle condition by histology and wet weight of the gastrocnemius and quadriceps. Both laser treatments reduced cartilage degeneration and improved weight-bearing. The 10 mW group showed greater improvements than the 20 mW group, including higher proteoglycan content, better bone structural parameters, and greater muscle mass. These results indicate that 10 mW laser acupuncture is more effective than 20 mW in reducing joint damage and preserving musculoskeletal tissue. The findings support the use of low-power laser acupuncture as a non-invasive treatment for OA. The study also shows that higher laser power does not necessarily lead to better outcomes, highlighting the need for appropriate dose selection. Further studies are needed to assess long-term effects and investigate underlying mechanisms.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101864"},"PeriodicalIF":2.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144770959","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
期刊
Bone Reports
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