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3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: From monoclonal gammopathy to newly diagnosed multiple myeloma 利用高分辨率显微 CT 对人体骨活检组织进行三维骨细胞裂隙形态测量:从单克隆抗体病到新诊断的多发性骨髓瘤。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-14 DOI: 10.1016/j.bone.2024.117236
Inés Moreno-Jiménez , Sharen Heinig , Unai Heras , Daniela Simone Maichl , Susanne Strifler , Ellen Leich , Stéphane Blouin , Peter Fratzl , Nadja Fratzl-Zelman , Franziska Jundt , Amaia Cipitria

Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites. Qualitative and quantitative changes in the 3D osteocyte lacunar morphometry have not yet been evaluated in MM, nor in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). In this study, we characterized the osteocyte lacunar morphology in trabecular bone of the iliac crest at the ultrastructural level using high resolution microCT in human bone biopsy samples of three MGUS, two SMM and six newly diagnosed MM. In MGUS, SMM and MM we found a trend for lower lacunar density and a shift towards larger lacunae with disease progression (higher 50 % cutoff of the lacunar volume cumulative distribution) in the small osteocyte lacunae 20–900 μm3 range compared to control samples. In the larger lacunae 900–3000 μm3 range, we detected significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae density, volume and shape, which could be an indicator for osteolysis and disease progression. Future studies are needed to understand whether alterations of the lacunae architecture affect the mechanoresponsiveness of osteocytes, and ultimately bone adaptation and fracture resistance in MM and its precursors conditions.

骨细胞是对机械敏感的骨嵌入细胞,通过树突连接成裂隙-管状网络,调节骨吸收和形成的平衡。在衰老、骨质疏松症和溶骨性骨转移等情况下,已发现骨细胞裂隙体积、形状和密度发生变化,表明骨重塑、溶骨和疾病进展的模式受损。溶骨性骨病是血液系统恶性肿瘤多发性骨髓瘤(MM)的特征之一,骨髓中的单克隆浆细胞会破坏骨平衡,诱发局部和远处部位的过度吸收。目前尚未对多发性骨髓瘤三维骨细胞裂隙形态的定性和定量变化进行评估,也未对意义未定的单克隆性淋巴瘤(MGUS)和烟雾型多发性骨髓瘤(SMM)的前驱症状进行评估。在这项研究中,我们利用高分辨率显微 CT 技术,从超微结构层面描述了 3 例 MGUS、2 例 SMM 和 6 例新确诊 MM 的人体骨活检样本中髂嵴骨小梁中的骨细胞裂隙形态。在 MGUS、SMM 和 MM 中,与对照样本相比,我们发现随着疾病的发展(裂隙体积累积分布的 50% 临界值更高),在 20-900 μm3 范围内的小骨细胞裂隙中,裂隙密度呈降低趋势,并向更大的裂隙转变。在900-3000 μm3范围的较大腔隙中,我们发现MM组的腔隙密度和微孔率明显高于MGUS/SMM组。在形状分布方面,与对照组相比,MGUS/SMM 组的骨细胞腔呈扁平、拉长和各向异性趋势。总之,我们的研究结果表明,人类MM骨病患者的骨细胞腔密度、体积和形状会发生变化,这可能是溶骨和疾病进展的一个指标。未来的研究需要了解腔隙结构的改变是否会影响骨细胞的机械敏感性,并最终影响 MM 及其前体病变中骨的适应性和抗骨折性。
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引用次数: 0
Mitigating aging and doxorubicin induced bone loss in mature mice via mechanobiology based treatments 通过基于机械生物学的疗法缓解成熟小鼠的衰老和多柔比星诱导的骨质流失。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-13 DOI: 10.1016/j.bone.2024.117235
Murtaza Wasi , Tiankuo Chu , Rosa M. Guerra , Rory Kooker , Kenneth Maldonado , Xuehua Li , Chun-Yu Lin , Xin Song , Jinhu Xiong , Lidan You , Liyun Wang

Aging leads to a reduced anabolic response to mechanical stimuli and a loss of bone mass and structural integrity. Chemotherapy agents such as doxorubicin exacerbate the degeneration of aging skeleton and further subject older cancer patients to a higher fracture risk. To alleviate this clinical problem, we proposed and tested a novel mechanobiology-based therapy. Building upon prior findings that i) Yoda1, the Piezo1 agonist, promoted bone growth in young adult mice and suppressed bone resorption markers in aged mice, and ii) moderate tibial loading protected bone from breast cancer-induced osteolysis, we hypothesized that combined Yoda1 and moderate loading would improve the structural integrity of adult and aged skeletons in vivo and protect bones from deterioration after chemotherapy. We first examined the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles for 5 days/week), individually and combined, on mature mice (∼50 weeks of age). Combined Yoda1 and loading was found to mitigate age-associated cortical and trabecular bone loss better than individual interventions. As expected, the non-treated controls experienced an average drop of cortical polar moment of inertia (Ct.pMOI) by −4.3 % over four weeks and the bone deterioration occurred in the majority (64 %) of the samples. Relative to no treatment, loading alone, Yoda1 alone, and combined Yoda1 and loading increased Ct.pMOI by +7.3 %, +9.5 %, +12.0 % and increased the % of samples with positive Ct.pMOI changes by +32 %, +26 %, and +43 %, respectively, suggesting an additive protection of aging-related bone loss for the combined therapy. We further tested if the treatment efficacy was preserved in mature mice following two weeks (six injections) of doxorubicin at the dose of 2.5 or 5 mg/kg. As expected, doxorubicin increased osteocyte apoptosis, altered bone remodeling, and impaired bone structure. However, the effects induced by DOX were too severe to be rescued by Yoda1 and loading, alone or combined, although loading and Yoda1 individually, or combined, increased the number of mice showing positive responsiveness by 0 %, +15 %, and +29 % relative to no intervention after doxorubicin exposure. Overall, this study supported the potentials and challenges of the Yoda1-based strategy in mitigating the detrimental skeletal effects caused by aging and doxorubicin.

衰老会导致对机械刺激的合成代谢反应减弱,骨质和结构完整性丧失。多柔比星等化疗药物会加剧衰老骨骼的退化,使老年癌症患者面临更高的骨折风险。为了缓解这一临床问题,我们提出并测试了一种基于机械生物学的新型疗法。基于之前的研究结果(i)Piezo1 激动剂 Yoda1 促进了年轻成年小鼠的骨生长并抑制了老年小鼠的骨吸收标记物;(ii)适度的胫骨负荷保护了骨骼免受乳腺癌诱导的骨溶解的影响),我们假设 Yoda1 和适度负荷相结合将改善体内成年和老年骨骼的结构完整性并保护骨骼免受化疗后的退化。我们首先对成年小鼠(约 50 周龄)进行了为期 4 周的 Yoda1(剂量为 5 毫克/千克,5 次/周)和适度胫骨负荷(峰值负荷为 4.5 牛,4 赫兹,300 个周期,5 天/周)的单独或联合试验。研究发现,Yoda1和加载相结合比单独干预能更好地缓解年龄相关的皮质和骨小梁骨质流失。不出所料,未接受治疗的对照组在四周内皮质极惯性矩(Ct.pMOI)平均下降了-4.3%,大多数样本(64%)的骨质都出现了退化。与不治疗相比,单独加载、单独Yoda1以及Yoda1和加载联合疗法可使Ct.pMOI分别增加7.3%、9.5%和12.0%,并使Ct.pMOI发生正向变化的样本比例分别增加32%、26%和43%,这表明联合疗法对衰老相关的骨质流失具有叠加保护作用。我们进一步测试了成熟小鼠在接受 2.5 或 5 毫克/千克剂量的多柔比星治疗两周(注射六次)后是否能保持疗效。不出所料,多柔比星会增加骨细胞凋亡、改变骨重塑和损害骨结构。然而,DOX诱导的影响过于严重,Yoda1和负载(单独或联合使用)都无法挽救,尽管负载和Yoda1单独或联合使用,相对于暴露于多柔比星后未进行干预,显示阳性反应的小鼠数量分别增加了0%、+15%和+29%。总之,这项研究证实了基于 Yoda1 的策略在减轻衰老和多柔比星对骨骼造成的有害影响方面的潜力和挑战。
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引用次数: 0
A GCaMP reporter mouse with chondrocyte specific expression of a green fluorescent calcium indicator 特异性表达软骨细胞绿色荧光钙指示剂的 GCaMP 报告小鼠
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-13 DOI: 10.1016/j.bone.2024.117234
Sotirios A. Tsadaris , David E. Komatsu , Vladimir Grubisic , Raddy L. Ramos , Michael Hadjiargyrou

One of the major processes occurring during the healing of a fractured long bone is chondrogenesis, leading to the formation of the soft callus, which subsequently undergoes endochondral ossification and ultimately bridges the fracture site. Thus, understanding the molecular mechanisms of chondrogenesis can enhance our knowledge of the fracture repair process. One such molecular process is calciun (Ca++) signaling, which is known to play a critical role in the development and regeneration of multiple tissues, including bone, in response to external stimuli. Despite the existence of various mouse models for studying Ca++ signaling, none of them were designed to specifically examine the skeletal system or the various musculoskeletal cell types. As such, we generated a genetically engineered mouse model that is specific to cartilage (crossed with Col2a1 Cre mice) to study chondrocytes. Herein, we report on the characterization of this transgenic mouse line using conditional expression of GCaMP6f, a Ca++-indicator protein. Specifically, this mouse line exhibits increased GCaMP6f fluorescence following Ca++ binding in chondrocytes. Using this model, we show real-time Ca++ signaling in embryos, newborn and adult mice, as well as in fracture calluses. Further, robust expression of GCaMP6f in chondrocytes can be easily detected in embryos, neonates, adults, and fracture callus tissue sections. Finally, we also report on Ca++ signaling pathway gene expression, as well as real-time Ca++ transient measurements in fracture callus chondrocytes. Taken together, these mice provide a new experimental tool to study chondrocyte-specific Ca++ signaling during skeletal development and regeneration, as well as various in vitro perturbations.

软骨生成是长骨骨折愈合过程中发生的主要过程之一,它导致软茧的形成,软茧随后发生软骨内骨化,最终在骨折部位形成桥接。因此,了解软骨生成的分子机制可以增进我们对骨折修复过程的了解。众所周知,钙离子(Ca++)信号传导在包括骨骼在内的多种组织的发育和再生过程中对外界刺激起着至关重要的作用。尽管存在各种研究 Ca++ 信号传导的小鼠模型,但它们都不是专门为研究骨骼系统或各种肌肉骨骼细胞类型而设计的。因此,我们生成了一种专门针对软骨的基因工程小鼠模型(与 Col2a1 Cre 小鼠杂交)来研究软骨细胞。在此,我们报告了利用条件性表达钙离子指示蛋白 GCaMP6f 的转基因小鼠品系的特征。具体来说,该小鼠品系在软骨细胞与 Ca++ 结合后显示出更强的 GCaMP6f 荧光。利用这一模型,我们在胚胎、新生小鼠、成年小鼠以及骨折胼胝体中显示了实时 Ca++ 信号传导。此外,在胚胎、新生儿、成年小鼠和骨折胼胝体组织切片中都能轻松检测到软骨细胞中 GCaMP6f 的强表达。最后,我们还报告了Ca++信号通路基因的表达,以及骨折胼胝体软骨细胞中Ca++瞬态的实时测量。总之,这些小鼠为研究骨骼发育和再生过程中软骨细胞特异性 Ca++ 信号传导以及各种体外扰动提供了一种新的实验工具。
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引用次数: 0
Cross-sectional size, shape, and estimated strength of the tibia, fibula and second metatarsal in female collegiate-level cross-country runners and soccer players 女大学生越野跑运动员和足球运动员胫骨、腓骨和第二跖骨的横截面尺寸、形状和估计强度。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-09 DOI: 10.1016/j.bone.2024.117233
Austin M. Sventeckis , Rachel K. Surowiec , Robyn K. Fuchs , Stuart J. Warden

Bone stress injuries (BSIs) frequently occur in the leg and foot long bones of female distance runners. A potential means of preventing BSIs is to participate in multidirectional sports when younger to build a more robust skeleton. The current cross-sectional study compared differences in tibia, fibula, and second metatarsal diaphysis size, shape, and strength between female collegiate-level athletes specialized in cross-country running (RUN, n = 16) and soccer (SOC, n = 16). Assessments were performed using high-resolution peripheral quantitative computed tomography and outcomes corrected for measures at the radius diaphysis to control for selection bias and systemic differences between groups. The tibia in SOC had a 7.5 % larger total area than RUN, with a 29.4 % greater minimum second moment of area (IMIN) and 8.2 % greater estimated failure load (all p ≤ 0.02). Tibial values in SOC exceeded reference data indicating positive adaptation. In contrast, values in RUN were similar to reference data suggesting running induced limited tibial adaptation. RUN did have a larger ratio between their maximum second moment of area (IMAX) and IMIN than both SOC and reference values. This suggests the unidirectional loading associated with running altered tibial shape with material distributed more in the anteroposterior (IMAX) direction as opposed to the mediolateral (IMIN) direction. Comparatively, SOC had a similar IMAX/IMIN ratio to reference data suggesting the larger tibia in SOC resulted from multiplane adaptation. In addition to enhanced size and strength of their tibia, SOC had enhanced structure and strength of their fibula and second metatarsal. At both sites, polar moment of inertia was approximately 25 % larger in SOC compared to RUN (all p = 0.03). These data support calls for young female athletes to delay specialization in running and participate in multidirectional sports, like soccer, to build a more robust skeleton that is potentially more protected against BSIs.

女性长跑运动员的腿部和脚部长骨经常会出现骨应力损伤(BSI)。预防 BSI 的一个潜在方法是在年轻时参加多向运动,以建立更强健的骨骼。本横断面研究比较了专门从事越野跑(RUN,n = 16)和足球(SOC,n = 16)运动的女大学生运动员在胫骨、腓骨和第二跖骨干骺端的尺寸、形状和强度方面的差异。评估采用高分辨率外周定量计算机断层扫描,并对桡骨干骺端的测量结果进行校正,以控制选择偏差和组间系统性差异。SOC组的胫骨总面积比RUN组大7.5%,最小第二面积力矩(IMIN)比RUN组大29.4%,估计破坏负荷比RUN组大8.2%(所有P均≤0.02)。SOC 中的胫骨值超过了参考数据,表明适应性良好。相比之下,RUN 的值与参考数据相似,表明跑步引起的胫骨适应性有限。与 SOC 和参考值相比,RUN 的最大第二面积矩 (IMAX) 与 IMIN 之间的比率确实更大。这表明与跑步相关的单向负荷改变了胫骨形状,材料更多地分布在前胸(IMAX)方向,而不是内外侧(IMIN)方向。相比之下,SOC 的 IMAX/IMIN 比值与参考数据相似,这表明 SOC 中较大的胫骨是多平面适应的结果。除了胫骨的尺寸和强度得到增强外,SOC 的腓骨和第二跖骨的结构和强度也得到了增强。在这两个部位,SOC 的极惯性矩比 RUN 大约 25%(所有 p = 0.03)。这些数据支持了年轻女运动员推迟专门从事跑步并参加多方向运动(如足球)的呼吁,以建立更坚固的骨骼,从而更好地抵御 BSI。
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引用次数: 0
miR-18a-5p promotes osteogenic differentiation of BMSC by inhibiting Notch2 miR-18a-5p 通过抑制 Notch2 促进 BMSC 的成骨分化。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-06 DOI: 10.1016/j.bone.2024.117224
Peipei He , Zefeng Yang , Hetong Li , Enhui Zhou , Zuoxu Hou , Hongxun Sang

Postmenopausal osteoporosis (PMOP) is a metabolic disorder characterized by the loss of bone density, which increases the risk of developing complications such as fractures. A pivotal factor contributing to the onset of PMOP is the diminished osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs). MicroRNAs (miRNAs) play a substantial role in this process; however, their specific impact on regulating BMSCs osteogenesis remains unclear. Studies have evidenced a reduced expression of miR-18a-5p in PMOP, and concomitantly, our observations indicate an augmented expression of miR-18a-5p during the osteogenic differentiation of BMSCs. This investigation seeks to elucidate the regulatory influence of miR-18a-5p on BMSC osteogenic differentiation and the underlying mechanisms. In vitro experiments demonstrated that the overexpression of miR-18a-5p facilitated the osteogenic differentiation of BMSCs, while the downregulation of miR-18a-5p yielded converse outcomes. Mechanistically, We employed bioinformatics techniques to screen out the target gene Notch2 of miR-18a-5p. Subsequently, dual-luciferase reporter gene assays and rescue experiments substantiated that miR-18a-5p promotes BMSC osteogenic differentiation by suppressing Notch2. Finally, miR-18a-5p was overexpressed via adenovirus injection into the femoral bone marrow cavity, with results demonstrating its capability to enhance osteogenic differentiation and alleviate PMOP symptoms. Our findings disclose that miR-18a-5p fosters osteogenic differentiation of BMSC by inhibiting Notch2, thereby offering novel targets and strategies for PMOP treatment.

绝经后骨质疏松症(PMOP)是一种以骨密度丧失为特征的代谢性疾病,会增加发生骨折等并发症的风险。导致绝经后骨质疏松症发病的一个关键因素是骨髓间充质干细胞(BMSCs)的成骨分化能力减弱。微小核糖核酸(miRNA)在这一过程中发挥着重要作用;然而,它们对调节骨髓间充质干细胞成骨的具体影响仍不清楚。研究表明,在 PMOP 中,miR-18a-5p 的表达量减少,与此同时,我们的观察表明,在 BMSCs 成骨分化过程中,miR-18a-5p 的表达量增加。本研究旨在阐明 miR-18a-5p 对 BMSC 成骨分化的调控作用及其内在机制。体外实验表明,miR-18a-5p 的过表达促进了 BMSCs 的成骨分化,而 miR-18a-5p 的下调则产生相反的结果。从机理上讲,我们利用生物信息学技术筛选出了 miR-18a-5p 的靶基因 Notch2。随后,双荧光素酶报告基因实验和拯救实验证实,miR-18a-5p 通过抑制 Notch2 促进 BMSC 成骨分化。最后,miR-18a-5p通过腺病毒注射到股骨髓腔中进行过表达,结果表明它能促进成骨分化并缓解PMOP症状。我们的研究结果表明,miR-18a-5p 可通过抑制 Notch2 促进骨髓造血干细胞的成骨分化,从而为治疗 PMOP 提供了新的靶点和策略。
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引用次数: 0
Clinical frailty and short-term outcomes after low-energy pelvic fracture in the geriatric population: Nationwide inpatient sample 2016–2018 analysis 老年人低能量骨盆骨折后的临床虚弱和短期疗效:2016-2018年全国住院病人样本分析。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-06 DOI: 10.1016/j.bone.2024.117225
Yu-Cheng Lo , Chih-Hui Chen , Chiu Yu Shih , Omar Toma

Background

Pelvic fractures can be life-threatening for elderly individuals with diminished bone strength. Frailty is associated with fracture outcomes, but its impact on pelvic fracture recovery remains unexplored. The aim of this study was to investigate the association between frailty and short-term outcomes in older adults hospitalized for low-energy pelvic fractures.

Methods

Data from the Nationwide Inpatient Sample (NIS) covering the years 2005 to 2018 were reviewed. Inclusion criteria were age ≥ 60 years admitted for a low-energy pelvic fracture. Patients were categorized into frail and non-frail groups using the 11-factor modified Frailty Index (mFI-11). Association between frailty and in-hospital outcomes were determined by univariate and multivariable regression analyses.

Results

A total of 24,688 patients with pelvic fractures were included. The mean patient age was 80.6 ± 0.1 years, and 35 % were classified as frail. After adjustments, frailty was significantly associated with unfavorable discharge (adjusted odds ratio [aOR] = 1.07, 95 % confidence interval [CI]: 1.00–1.15, p = 0.038), prolonged hospitalization (aOR = 1.51, 95 % CI: 1.41–1.62, p < 0.001), complications (aOR = 1.42, 95 % CI:1.34–1.50, p < 0.001), and acute kidney injury (aOR = 1.68, 95 % CI: 1.56–1.82, p < 0.001). Stratified analyses based on age and fracture type showed frailty was consistently associated with adverse outcomes.

Conclusions

Persons ≥60 years old with mFI-11 assessed frailty and a low-energy pelvic fracture are at higher risk of adverse in-hospital outcomes than non-frail patients. Additional research is needed to disclose the prognostic impact of clinical frailty on long-term functional outcomes and quality of life after discharge.

背景:骨盆骨折对骨质疏松的老年人来说可能会危及生命。虚弱与骨折结果有关,但其对骨盆骨折恢复的影响仍未得到探讨。本研究旨在调查因低能量骨盆骨折住院的老年人的虚弱程度与短期疗效之间的关系:研究回顾了 2005 年至 2018 年全国住院患者样本(NIS)的数据。纳入标准为因低能骨盆骨折住院的患者年龄≥60岁。采用11因子改良虚弱指数(mFI-11)将患者分为虚弱组和非虚弱组。通过单变量和多变量回归分析确定虚弱与院内预后之间的关系:共纳入 24,688 名骨盆骨折患者。患者平均年龄为(80.6 ± 0.1)岁,35%的患者被归类为体弱者。经调整后,体弱与不利出院显著相关(调整后的几率比 [aOR] = 1.07,95% 置信区间 [CI]:1.00-1.15,P<0.05):1.00-1.15,p = 0.038)、住院时间延长(aOR = 1.51,95 % 置信区间[CI]:1.41-1.62,p 结论:≥60 岁的患者中,体弱者的比例最高:与非虚弱患者相比,经 mFI-11 评估为虚弱且发生低能量骨盆骨折的≥60 岁患者发生院内不良预后的风险更高。还需要进行更多的研究来揭示临床虚弱对出院后长期功能预后和生活质量的影响。
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引用次数: 0
Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes bone length, regulates cortical and trabecular bone mass, and maintains growth plate architecture and width in a sex- and site-specific manner in mice 耐酒石酸磷酸酶(TRAP/ACP5)以性别和部位特异性的方式促进小鼠骨长、调节皮质和骨小梁的骨量以及维持生长板的结构和宽度。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-05 DOI: 10.1016/j.bone.2024.117223
Bhavik Rathod , Suchita Desai , Hasmik Jasmine Samvelyan , Laura Bock , Jianyao Wu , Claes Ohlsson , Anders Palmquist , Jessica J. Alm , Phillip T. Newton , Göran Andersson , Sara H. Windahl

Tartrate-resistant acid phosphatase (TRAP) serum levels reflect osteoclast number, bone remodeling activity, and fracture risk. Deletion or loss of function of TRAP results in short stature in mice and man. Yet, the impact and mechanisms of TRAP for the site- and sex-specific development of bone and cartilage is not well understood. Here, we use a global TRAP knockout (TRAPKO) and wildtype littermate control (WT) mice of both sexes to investigate TRAP as a possible sex- and site-specific regulator of bone and growth plate development. TRAPKO mice of both sexes weighed less and had shorter tibial length than their WT, features that were more accentuated in male than female TRAPKO mice. These changes were not associated with a general reduction in growth as not all organs displayed a proportionally lower mass, and serum IGF-1 was unchanged. Using μCT and site-specificity analysis of the cortical bone revealed wider proximal tibia, a higher trabecular thickness, and lower trabecular separation in male TRAPKO compared to WT mice, an effect not seen in female mice. Histomorphometric analysis revealed that the growth plate height as well as height of terminal hypertrophic chondrocytes were markedly increased, and the number of columns was decreased in TRAPKO mice of both sexes. These effects were more accentuated in female mice. Proliferation and differentiation of bone marrow derived macrophages into osteoclasts, as well as C-terminal cross links were normal in TRAPKO mice of both sexes. Collectively, our results show that TRAP regulates bone and cartilage development in a sex-and site-specific manner in mice.

抗酒石酸磷酸酶(TRAP)血清水平反映了破骨细胞数量、骨重塑活性和骨折风险。TRAP 的缺失或功能丧失会导致小鼠和人类身材矮小。然而,TRAP 对骨骼和软骨的部位和性别特异性发育的影响和机制尚不十分清楚。在这里,我们利用全基因组TRAP基因敲除(TRAPKO)小鼠和野生型同窝对照(WT)小鼠来研究TRAP可能是骨骼和生长板发育的性别和部位特异性调节因子。与WT小鼠相比,TRAPKO小鼠的体重更轻,胫骨长度更短。这些变化与生长的普遍降低无关,因为并非所有器官的质量都按比例降低,而且血清 IGF-1 也没有变化。通过对皮质骨进行μCT和位点特异性分析,发现与WT小鼠相比,雄性TRAPKO小鼠的胫骨近端更宽、骨小梁厚度更高、骨小梁分离度更低,而雌性小鼠则没有这种效应。组织形态学分析表明,TRAPKO 小鼠的生长板高度和末端肥大软骨细胞高度明显增加,而雌雄小鼠的骨柱数量均减少。这些影响在雌性小鼠中更为明显。TRAPKO小鼠的骨髓巨噬细胞增殖和分化为破骨细胞以及C端交叉连接均正常。总之,我们的研究结果表明,TRAP以性别和部位特异性的方式调节小鼠骨骼和软骨的发育。
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引用次数: 0
Estrogen and estrogen receptors mediate the mechanobiology of bone disease and repair 雌激素和雌激素受体介导骨病和修复的机械生物学。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-05 DOI: 10.1016/j.bone.2024.117220
Vivian Shi, Elise F. Morgan

It is well understood that the balance of bone formation and resorption is dependent on both mechanical and biochemical factors. In addition to cell-secreted cytokines and growth factors, sex hormones like estrogen are critical to maintaining bone health. Although the direct osteoprotective function of estrogen and estrogen receptors (ERs) has been reported extensively, evidence that estrogen signaling also has a role in mediating the effects of mechanical loading on maintenance of bone mass and healing of bone injuries has more recently emerged. Recent studies have underscored the role of estrogen and ERs in many pathways of bone mechanosensation and mechanotransduction. Estrogen and ERs have been shown to augment integrin-based mechanotransduction as well as canonical Wnt/b-catenin, RhoA/ROCK, and YAP/TAZ pathways. Estrogen and ERs also influence the mechanosensitivity of not only osteocytes but also osteoblasts, osteoclasts, and marrow stromal cells. The current review will highlight these roles of estrogen and ERs in cellular mechanisms underlying bone mechanobiology and discuss their implications for management of osteoporosis and bone fractures. A greater understanding of the mechanisms behind interactions between estrogen and mechanical loading may be crucial to addressing the shortcomings of current hormonal and pharmaceutical therapies. A combined therapy approach including high-impact exercise therapy may mitigate adverse side effects and allow an effective long-term solution for the prevention, treatment, and management of bone fragility in at-risk populations. Furthermore, future implications to novel local delivery mechanisms of hormonal therapy for osteoporosis treatment, as well as the effects on bone health of applications of sex hormone therapy outside of bone disease, will be discussed.

众所周知,骨骼形成和吸收的平衡取决于机械和生化因素。除了细胞分泌的细胞因子和生长因子外,雌激素等性激素对维持骨骼健康也至关重要。尽管雌激素和雌激素受体(ERs)的直接骨保护功能已被广泛报道,但最近出现的证据表明,雌激素信号传导还在介导机械负荷对骨量维持和骨损伤愈合的影响方面发挥作用。最近的研究强调了雌激素和雌激素受体在骨机械感觉和机械传导的许多途径中的作用。研究表明,雌激素和雌激素可增强基于整合素的机械传导,以及典型的 Wnt/b-catenin、RhoA/ROCK 和 YAP/TAZ 通路。雌激素和ERs不仅影响成骨细胞的机械敏感性,还影响成骨细胞、破骨细胞和骨髓基质细胞的机械敏感性。本综述将强调雌激素和雌激素在骨力学生物学基础细胞机制中的这些作用,并讨论它们对骨质疏松症和骨折治疗的影响。更深入地了解雌激素与机械负荷之间的相互作用机制可能对解决当前激素和药物疗法的不足之处至关重要。包括高强度运动疗法在内的综合疗法可减轻不良副作用,为高危人群预防、治疗和管理骨质疏松提供长期有效的解决方案。此外,还将讨论新的局部荷尔蒙疗法机制对骨质疏松症治疗的未来影响,以及性荷尔蒙疗法在骨病之外的应用对骨骼健康的影响。
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引用次数: 0
Zoledronic acid relieves steroid-induced avascular necrosis of femoral head via inhibiting FOXD3 mediated ANXA2 transcriptional activation 唑来膦酸通过抑制 FOXD3 介导的 ANXA2 转录激活,缓解类固醇诱导的股骨头血管性坏死。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-03 DOI: 10.1016/j.bone.2024.117222
Yu Lin , Min Chen , Wenbin Guo , Shengliang Qiu , Lihui Chen , Wenge Liu

Background

Zoledronic acid (ZOL) is a type of bisphosphonate with good therapeutic effects on orthopaedic diseases. However, the pharmacological functions of ZOL on steroid-induced avascular necrosis of femoral head (SANFH) and the underlying mechanism remain unclear, which deserve further research.

Methods

SANFH models both in vivo and in vitro were established by dexamethasone (Dex) stimulation. Osteoclastogenesis was examined by TRAP staining. Immunofluorescence was employed to examine autophagy marker (LC3) level. Cell apoptosis was analyzed by TUNEL staining. The interaction between Foxhead box D3 protein (FOXD3) and Annexin A2 (ANXA2) promoter was analyzed using ChIP and dual luciferase reporter gene assays.

Results

Dex aggravated osteoclastogenesis and induced osteoclast differentiation and autophagy in vitro, which was abrogated by ZOL treatment. PI3K inhibitor LY294002 abolished the inhibitory effect of ZOL on Dex-induced osteoclast differentiation and autophagy. FOXD3 overexpression neutralized the downregulation effects of ZOL on Dex-induced osteoclasts by transcriptionally activating ANXA2. ANXA2 knockdown reversed the effect of FOXD3 overexpression on ZOL-mediated biological effects in Dex-treated osteoclasts. In addition, ZOL improved SANFH symptoms in rats.

Conclusion

ZOL alleviated SANFH through regulating FOXD3 mediated ANXA2 transcriptional activity and then promoting PI3K/AKT/mTOR pathway, revealing that FOXD3 might be a target for ZOL in SANFH treatment.

背景:唑来膦酸(ZOL)是一种双膦酸盐,对骨科疾病具有良好的治疗效果。然而,唑来膦酸对类固醇诱导的股骨头血管性坏死(SANFH)的药理作用及其内在机制仍不清楚,值得进一步研究:方法:通过地塞米松(Dex)刺激建立体内和体外股骨头坏死模型。方法:通过地塞米松(Dex)刺激建立体内和体外的 SANFH 模型。免疫荧光法检测自噬标记物(LC3)水平。通过TUNEL染色分析细胞凋亡。利用ChIP和双荧光素酶报告基因实验分析了Foxhead box D3蛋白(FOXD3)和Annexin A2(ANXA2)启动子之间的相互作用:结果:Dex可加重破骨细胞的生成,并诱导体外破骨细胞分化和自噬,ZOL处理可减轻这种作用。PI3K抑制剂LY294002可消除ZOL对Dex诱导的破骨细胞分化和自噬的抑制作用。FOXD3的过表达通过转录激活ANXA2中和了ZOL对Dex诱导的破骨细胞的下调作用。ANXA2 敲除逆转了 FOXD3 过表达对 ZOL 介导的 Dex 治疗破骨细胞生物效应的影响。此外,ZOL还能改善大鼠的SANFH症状:结论:ZOL通过调节FOXD3介导的ANXA2转录活性,进而促进PI3K/AKT/mTOR通路,缓解了SANFH,揭示了FOXD3可能是ZOL治疗SANFH的靶点。
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引用次数: 0
Clinical and radiological response of Maffucci related enchondromas to mutant IDH1 inhibitor Ivosidenib 马夫奇相关软骨瘤对突变 IDH1 抑制剂 Ivosidenib 的临床和放射学反应。
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-02 DOI: 10.1016/j.bone.2024.117221
Thomas Funck-Brentano , Martine Cohen-Solal , François Ducray , Emmanuel Mandonnet

Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.

奥利尔病(Ollier Disease,OD)和马福奇综合征(Maffucci Syndrome,MS)是一种影响骨骼生长和发育的罕见骨骼疾病,发病率约为十万分之一。它与异柠檬酸脱氢酶-1(IDH1)或2(IDH2)致病变体的体细胞嵌合有关。伊沃西地尼适用于治疗急性髓性白血病和局部晚期或转移性胆管癌,目前正在对具有易感异柠檬酸脱氢酶-1(IDH1)致病变体的低级别胶质瘤进行研究,但其对OD或MS患者的影响尚不清楚。我们在此报告了首例接受伊沃西地尼治疗的复发性 IDH-1 突变胶质瘤 MS 患者的病例。除了肿瘤大小趋于稳定外,患者的软骨瘤也有了明显改善,变得更加硬朗,疼痛减轻,X 光片上观察到软骨瘤的矿化也有了明显改变。这第一份病例报告为因骨质疏松症或多发性硬化症而遭受痛苦的患者的医疗管理带来了希望。未来的临床研究迫切需要评估 IDH 抑制剂在这些罕见疾病中的长期获益风险情况。
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引用次数: 0
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