IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-10-09 DOI: 10.1016/j.bone.2024.117274

Ana Rachel Teixeira Batista Carvalho , Daniel Humberto Dias Freire , Alaor Barra Sobrinho , Angélica Amorim Amato

Hypoparathyroidism is a rare disease that markedly reduces bone remodeling, leading to increased bone mineral density and changes in bone microarchitecture. However, it is currently unclear how these changes affect fracture risk. In this study, we investigated bone mass by dual-energy x-ray absorptiometry, the occurrence of morphometric vertebral fractures, and bone microarchitecture by assessing trabecular bone score in women with postsurgical hypoparathyroidism. We included 67 women with hypoparathyroidism aged 52.9 ± 12.3 years and 63 age- and body mass index-matched controls, which were assessed for femoral and lumbar spine bone mineral density, trabecular bone score, and vertebral fractures by dual-energy x-ray absorptiometry. Women with hypoparathyroidism had significantly higher bone mineral density at the lumbar spine, femoral neck, and total hip compared with controls despite similar trabecular bone score values. Vertebral fracture assessment indicated that two women with hypoparathyroidism presented vertebral fractures, both aged over 65 years. Conversely, no vertebral fractures were detected in control women. In a multivariate linear regression model, we found that older age, diabetes, and lower lumbar spine mineral density were significant predictors of lower trabecular bone score values. Our findings indicate that vertebral fractures are not common among women with postsurgical hypoparathyroidism aged under 65 years. Moreover, trabecular bone score values were similar in women with hypoparathyroidism and age-matched controls and were associated with traditional risk factors for fractures, such as older age, type 2 diabetes, and lower spine bone mineral density.

Lay summary

Chronic parathyroid hormone deficiency decreases bone turnover and modifies skeletal properties, although the impact of these changes on fracture risk remains unclear. We studied 67 women with postsurgical hypoparathyroidism and 63 age and body mass index-matched healthy controls and found that bone mineral density is increased in women with hypoparathyroidism despite similar trabecular bone score values and a low occurrence of morphometric vertebral fractures. This suggests that the low bone turnover in hypoparathyroidism increases bone mass, but this is not accompanied by improved bone microarchitecture, indicating that trabecular bone score may be a valuable tool to complement the assessment of skeletal health and the risk of fractures in this condition.

甲状旁腺功能减退症是一种罕见的疾病，它会显著降低骨重塑，导致骨矿物质密度增加和骨微结构的改变。然而，目前还不清楚这些变化如何影响骨折风险。在这项研究中，我们通过双能量X射线吸收测量法调查了甲状旁腺功能减退症术后女性患者的骨量、椎体骨折的形态发生率，以及通过评估骨小梁得分调查的骨微结构。我们纳入了67名年龄为（52.9±12.3）岁的甲状旁腺功能减退症女性患者和63名年龄（52.9±12.3）岁、体重指数相匹配的对照组患者，通过双能X射线吸收测量法评估了她们的股骨和腰椎骨矿物质密度、骨小梁得分和椎体骨折情况。与对照组相比，患有甲状旁腺功能减退症的妇女在腰椎、股骨颈和全髋部的骨质密度明显更高，尽管骨小梁评分值与对照组相似。椎体骨折评估显示，两名甲状腺功能减退症妇女出现椎体骨折，年龄均超过 65 岁。相反，对照组妇女没有发现脊椎骨折。在多变量线性回归模型中，我们发现年龄较大、糖尿病和腰椎矿物质密度较低是导致骨小梁评分值降低的重要预测因素。我们的研究结果表明，在65岁以下患有甲状旁腺功能减退症的术后妇女中，脊椎骨折并不常见。此外，甲状旁腺功能减退症女性患者的骨小梁评分值与年龄匹配的对照组相似，并且与骨折的传统风险因素有关，如年龄较大、2型糖尿病和较低的脊椎骨矿物质密度。LAY总结：长期甲状旁腺激素缺乏会降低骨转换率并改变骨骼特性，但这些变化对骨折风险的影响仍不清楚。我们研究了67名手术后甲状旁腺功能减退症女性患者和63名年龄与体重指数相匹配的健康对照者，结果发现，尽管甲状旁腺功能减退症女性患者的骨小梁评分值相似，且形态学上的脊椎骨折发生率较低，但她们的骨矿密度却有所增加。这表明，甲状旁腺功能减退症患者的骨转换率低，从而增加了骨量，但这并没有伴随着骨微结构的改善。

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引用次数: 0

Effects of dopaminergic neuron degeneration on osteocyte apoptosis and osteogenic markers in 6-OHDA male rat model of Parkinson's disease 多巴胺能神经元变性对 6-OHDA 雄性帕金森病大鼠骨细胞凋亡和成骨标志物的影响

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-10-05 DOI: 10.1016/j.bone.2024.117271

Latifa Knani , Massimo Venditti , Hajer Rouis , Sergio Minucci , Imed Messaoudi

Parkinson's disease (PD) and osteoporosis are prevalent chronic conditions that impact a significant proportion of the aging population. Observational and longitudinal studies consistently demonstrate that individuals with PD face an elevated risk of osteoporosis and reduced bone mineral density compared to control groups. However, there is currently no experimental evidence demonstrating the impact of dopaminergic neuron degeneration on bone metabolism. In the present study, we used a male rat model of PD induced by unilateral injection of 6-hydroxydopamine (6-OHDA) in the left medial forebrain bundle (MFB) to evaluate the effect of dopaminergic neuron lesion on certain parameters of bone metabolism. To confirm the dopaminergic neuron lesion, cylinder and Rotarod tests were applied to rats injected with 6-OHDA or vehicle. Osteocyte density and viability were determined through histology and TUNEL assay. Western Blot and immunohistochemistry analysis were performed to investigate whether dopaminergic degeneration influences the expression of some apoptotic markers (Caspase 3 and Cytochrome C) and some osteogenic markers (ALP, OCN, and RUNX2). Our findings show that the dopaminergic lesion resulting from the injection of 6-OHDA was successfully confirmed through behavioral tests. Furthermore, the degeneration of dopaminergic neurons induced by 6-OHDA leads to apoptosis of osteocytes associated with a significant reduction in the tissue expression of the studied osteogenic markers. Thus, our study provides evidence that 6-OHDA-induced degeneration of dopaminergic neurons leads to osteocyte apoptosis, which may contribute to the development of some signs of osteoporosis.

帕金森病（Parkinson's disease，PD）和骨质疏松症是普遍存在的慢性疾病，影响着很大一部分老龄人口。观察性和纵向研究一致表明，与对照组相比，帕金森病患者面临骨质疏松症和骨矿物质密度降低的风险更高。然而，目前还没有实验证据证明多巴胺能神经元变性对骨代谢的影响。在本研究中，我们利用雄性大鼠左侧前脑内侧束单侧注射6-羟基多巴胺（6-OHDA）诱导的帕金森病模型，评估多巴胺能神经元病变对骨代谢某些参数的影响。为证实多巴胺能神经元损伤，对注射了6-OHDA或药物的大鼠进行了圆柱体和旋转体试验。通过组织学和 TUNEL 检测确定骨细胞密度和存活率。通过Western印迹和免疫组化分析，研究多巴胺能变性是否会影响一些凋亡标志物（Caspase 3和细胞色素C）和一些成骨标志物（ALP、OCN和RUNX2）的表达。我们的研究结果表明，注射6-OHDA导致的多巴胺能损伤已通过行为测试得到证实。此外，6-OHDA 诱导的多巴胺能神经元变性会导致骨细胞凋亡，与此同时，所研究的成骨标志物的组织表达也会显著减少。因此，我们的研究提供的证据表明，6-OHDA诱导的多巴胺能神经元变性会导致骨细胞凋亡，这可能会导致骨质疏松症的某些症状的发生。

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引用次数: 0

Aerobic exercise training-induced bone and vascular adaptations in mice lacking adiponectin 有氧运动训练诱导缺乏脂肪连通素的小鼠骨骼和血管适应。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-10-05 DOI: 10.1016/j.bone.2024.117272

Hyerim Park , Samuel P. Trupiano , Steven L. Medarev , Payal Ghosh , Jacob T. Caldwell , Joshua F. Yarrow , Judy M. Muller-Delp

Adiponectin regulates lipid and glucose metabolism, and insulin sensitivity in various target organs; however, the effects of adiponectin on bone health remain controversial. Exercise training can enhance bone density, bone microarchitecture, and blood flow. This study aimed to elucidate the role of adiponectin in adaptations of bone microarchitecture and bone vasculature in response to aerobic exercise training.

Adult male C57BL/6 wild-type (WT) and homozygous adiponectin knockout (AdipoKO) mice were either treadmill exercise trained or remained sedentary for 8–10 weeks. The trabecular structures of the distal femoral metaphysis, a weight-bearing bone, and the mandible, a non-weight-bearing bone, were examined using microcomputed tomography. The femoral principal nutrient arteries were isolated to assess vasoreactivity (vasodilation and vasoconstriction) and structural remodeling.

At the femoral metaphysis, impaired trabecular bone structures, including reduced connectivity density and increased trabecular spacing, were observed in AdipoKO mice compared to WT mice. In addition, nitric oxide-mediated, endothelium-dependent vasodilation was substantially reduced, and wall-to-lumen ratio was significantly increased in the femoral principal nutrient artery of AdipoKO mice. Interestingly, although exercise training-induced enhancements in trabecular connectivity density were observed at the femoral metaphysis of both WT and AdipoKO, increased vasoconstrictor responses were only observed in the femoral principal nutrient artery of WT mice, not in the AdipoKO mice. In mandibular trabecular bone, exercise training increased trabecular bone volume fraction (BV/TV, %) and intersection surface in the mandible of both WT and AdipoKO mice.

These findings indicate that adiponectin is crucial for maintaining normal bone microarchitecture and vasculature. Although the absence of adiponectin compromises bone vascular adaptation to exercise training in mice, some exercise training-induced alterations in bone microarchitecture occurred in the absence of adiponectin, suggesting contribution of compensatory mechanisms during exercise training.

脂肪连通素能调节脂质和葡萄糖代谢，以及各目标器官对胰岛素的敏感性；然而，脂肪连通素对骨骼健康的影响仍存在争议。运动训练可增强骨密度、骨微结构和血流量。本研究旨在阐明有氧运动训练对骨微结构和骨血管适应性的影响。成年雄性C57BL/6野生型（WT）小鼠和同源基因脂肪连接素基因敲除（AdipoKO）小鼠均接受了8-10周的跑步机运动训练或静止不动。使用微计算机断层扫描技术对负重骨--股骨远端干骺端和非负重骨--下颌骨的骨小梁结构进行了检测。对股骨主要营养动脉进行分离，以评估血管活性（血管扩张和血管收缩）和结构重塑。与 WT 小鼠相比，AdipoKO 小鼠的股骨干骺端骨小梁结构受损，包括连接密度降低和骨小梁间距增大。此外，一氧化氮介导的、内皮依赖性血管舒张功能大大降低，AdipoKO 小鼠股主要营养动脉的管壁与管腔比率显著增加。有趣的是，虽然在 WT 小鼠和 AdipoKO 小鼠的股骨干骺端观察到运动训练诱导的骨小梁连接密度增强，但只在 WT 小鼠的股骨主要营养动脉中观察到血管收缩反应增强，而在 AdipoKO 小鼠中没有观察到。在下颌骨骨小梁中，运动训练增加了 WT 和 AdipoKO 小鼠下颌骨骨小梁体积分数（BV/TV，%）和交汇面。这些发现表明，脂肪连通素对维持正常的骨微结构和血管至关重要。虽然缺乏脂肪连通素会影响小鼠骨血管对运动训练的适应性，但在缺乏脂肪连通素的情况下，一些运动训练引起的骨微结构改变也会发生，这表明运动训练过程中存在代偿机制。

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引用次数: 0

A systematic review of mesenchymal stem cell secretome: Functional annotations, gene clusters and proteomics analyses for bone formation 间充质干细胞分泌组系统综述：骨形成的功能注释、基因簇和蛋白质组学分析。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-10-04 DOI: 10.1016/j.bone.2024.117269

Dia Advani , Nouran Farid , Muhammad Hamza Tariq , Nupur Kohli

The regenerative capacity of mesenchymal stem cells (MSCs) is now attributed to their ability to release paracrine factors into the extracellular matrix that boost tissue regeneration, reduce inflammation and encourage healing. Understanding the MSC secretome is crucial for shifting the prototypic conventional cell-based therapies to cell-free regenerative treatments. This systematic review aimed to analyse the functional annotations of the secretome of human adult adipose tissue and bone marrow MSCs and unveil the gene clusters responsible for bone formation. Bioinformatics tools were used to identify the biological processes, molecular functions, hallmarks and KEGG pathways of adipose and bone marrow MSC secretome proteins. We found a substantial overlap in the functional annotations and protein compositions of both adipose and bone marrow MSC secretome indicating that MSC source may be noninfluencial with regards to tissue regeneration. Additionally, a novel network pharmacology-based analysis of the secreted proteins revealed that the commonly secreted proteins within a single source interact with multiple drugable targets of bone diseases and regulate various KEGG pathway. This study unravels the secretome profile of human adult adipose and bone marrow MSCs based on the current literature and provides valuable insights into the therapeutic use of the MSC secretome for cell-free therapies.

间充质干细胞（MSCs）的再生能力目前归因于其向细胞外基质释放旁分泌因子的能力，这种能力可促进组织再生、减少炎症和促进愈合。了解间充质干细胞的分泌组对于将基于细胞的传统原型疗法转变为无细胞再生疗法至关重要。本系统综述旨在分析人类成人脂肪组织和骨髓间充质干细胞分泌组的功能注释，并揭示负责骨形成的基因簇。我们使用生物信息学工具识别了脂肪组织和骨髓间充质干细胞分泌组蛋白的生物学过程、分子功能、特征和 KEGG 通路。我们发现脂肪和骨髓间充质干细胞分泌组的功能注释和蛋白质组成有很大的重叠，这表明间充质干细胞的来源可能与组织再生无关。此外，一项基于网络药理学的新型分泌蛋白分析显示，单一来源中的常见分泌蛋白与骨病的多个药物靶点相互作用，并调控各种KEGG通路。这项研究在现有文献的基础上揭示了人类成体脂肪间充质干细胞和骨髓间充质干细胞的分泌组特征，为将间充质干细胞分泌组用于无细胞疗法提供了宝贵的见解。

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引用次数: 0

Bone loss after bariatric surgery is observed mainly in the hip trabecular compartment and after hypoabsorptive techniques 减肥手术后的骨质流失主要发生在髋关节小梁区和采用低吸收技术后。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-10-03 DOI: 10.1016/j.bone.2024.117270

Carmen Gómez-Vaquero , Mirella López Picazo , Ludovic Humbert , Laura Hernández-Montoliu , Olga Jermakova , Lydia Huanuco , Mishell Silva , Javier Osorio , Claudio Lazzara , Lucía Sobrino , Fernando Guerrero-Pérez , Nuria Vilarrasa

We evaluated the impact of bariatric surgery on bone mineral density (BMD) and microarchitecture over one year using dual-energy X-ray absorptiometry (DXA), the trabecular bone score (TBS), and 3D-DXA to assess changes after different surgical techniques. This prospective, single-center study of 153 patients with severe obesity contrasts the effects on bone health of sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and duodenal switch/single anastomosis duodeno-ileostomy with sleeve gastrectomy (DS/SADIS). To our knowledge, this is the first study to evaluate patients undergoing DS/SADIS and to incorporate 3D-DXA analysis in the assessment of bone loss.

Patients were 81 % female with a mean age of 50 ± 9 years. Fifty-four per cent underwent SG; 16 %, RYGB; and 30 %, DS/SADIS. Our findings revealed a significant decrease in areal BMD at the LS (−3.49 ± 5.44 %), FN (−5.24 ± 5.86 %), and TH (−8.06 ± 5.14 %) one year after bariatric surgery. Bone microarchitecture at the LS assessed by TBS was degraded in 30 % of patients. Proximal femur 3D-DXA analysis showed that surgery-induced bone loss predominantly affects the trabecular compartment (Trabecular volumetric (v) BMD: −8.00 ± 6.57 %) rather than the cortical compartment (Cortical vBMD: −1.37 ± 2.79 %).

These results suggest hypoabsorptive and mixed techniques (DS/SADIS and RYGB) were associated with greater BMD loss and deterioration of microarchitecture than restrictive techniques (SG).

The primary determinants of bone density and impairment of microarchitecture were the extent of weight loss and the type of surgical procedure. Despite overall bone loss, Z-score assessments indicated that post-surgical bone status remained within or above the average ranges compared to a healthy population, except for TH following DS/SADIS.

In conclusion, our research shows differences in the impact of bariatric surgery techniques on bone density and microarchitecture, emphasizing the need for careful postoperative monitoring of bone health, particularly in patients undergoing hypoabsorptive and mixed procedures.

我们使用双能 X 射线吸收测量法（DXA）、骨小梁评分法（TBS）和 3D-DXA 评估了减肥手术一年来对骨矿物质密度（BMD）和微结构的影响，以评估不同手术技术后的变化。这项前瞻性、单中心研究针对 153 名重度肥胖症患者，对比了袖状胃切除术（SG）、Roux-en-Y 胃旁路术（RYGB）和十二指肠转换/单吻合十二指肠回肠造口术加袖状胃切除术（DS/SADIS）对骨骼健康的影响。据我们所知，这是第一项对接受 DS/SADIS 手术的患者进行评估，并将 3D-DXA 分析纳入骨质流失评估的研究。患者中 81% 为女性，平均年龄为 50 ± 9 岁。54%的患者接受了 SG；16%接受了 RYGB；30%接受了 DS/SADIS。我们的研究结果显示，减肥手术一年后，LS（-3.49 ± 5.44 %）、FN（-5.24 ± 5.86 %）和TH（-8.06 ± 5.14 %）处的骨密度值明显下降。通过 TBS 评估，30% 的患者 LS 处的骨微结构退化。股骨近端 3D-DXA 分析显示，手术引起的骨质流失主要影响骨小梁区（骨小梁容积 (v) BMD：-8.00 ± 6.57 %），而非皮质区（皮质 vBMD：-1.37 ± 2.79 %）。这些结果表明，与限制性技术（SG）相比，低吸收性和混合性技术（DS/SADIS 和 RYGB）与更大的 BMD 损失和微结构恶化相关。骨密度和微结构损伤的主要决定因素是体重减轻程度和手术类型。尽管总体骨质流失，但 Z 值评估表明，与健康人群相比，手术后的骨质状况仍在平均范围内或高于平均范围，但 DS/SADIS 术后的 TH 除外。总之，我们的研究显示了减肥手术技术对骨密度和微结构影响的差异，强调了术后仔细监测骨健康的必要性，尤其是对接受低吸收手术和混合手术的患者。

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引用次数: 0

Meeting report from the 3rd ISCBH-ERN BOND Achondroplasia Workshop on Long Bone Pathology in Children with Achondroplasia, Salzburg, Austria 22nd June 2024 第三届 ISCBH-ERN BOND 儿童软骨发育症长骨病理学研讨会会议报告，奥地利萨尔茨堡，2024 年 6 月 22 日。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-10-02 DOI: 10.1016/j.bone.2024.117268

Moira S. Cheung , Inês Alves , Patricia Carl-Innig , Deborah Eastwood , Mohamad Maghnie , Amaka Offiah , Dror Paley , Simone Riganti , Ravi Savarirayan , Marco Sessa , Bjoern Vogt , Klaus Mohnike

A pre-meeting workshop on Long Bone Pathology in Children with Achondroplasia was held in Salzburg, Austria at the 11th International Conference on Children's Bone Health (ICCBH) 22–25 June 2024. There remains poor understanding and awareness amongst physicians managing achondroplasia of the underlying pathophysiology, radiology, natural history and orthopaedic procedures available for long bone deformities and restrictions. The structure of the workshop consisted of presentation of the results of a multinational patient survey on views of leg lengthening in achondroplasia, lectures, a debate and an interactive round table discussion. In total 150 attendees from 71 different cities and 31 countries were in attendance.

在 2024 年 6 月 22-25 日于奥地利萨尔茨堡举行的第 11 届国际儿童骨骼健康大会（ICCBH）上，举办了关于软骨发育不全儿童长骨病理学的会前研讨会。治疗软骨发育不全症的医生对其潜在的病理生理学、放射学、自然史以及针对长骨畸形和限制的矫形手术仍缺乏了解和认识。研讨会的内容包括：介绍一项关于软骨发育不全患者对腿部延长术的看法的跨国患者调查结果、演讲、辩论和圆桌互动讨论。共有来自 31 个国家 71 个城市的 150 名与会者出席了会议。

引用次数: 0

The association between fracture and short-term adverse health outcomes among children with cerebral palsy 脑瘫儿童骨折与短期不良健康后果之间的关联。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-10-02 DOI: 10.1016/j.bone.2024.117267

Daniel G. Whitney , Noelle S.B. Whyte , Michelle S. Caird

Background

Children with cerebral palsy (CP) have a high risk of fracture; yet, little is known about their post-fracture health outcomes. A fracture is an unplanned event in contrast to surgeries or procedures where there is a pre-operative period to optimize body composition and health and planned post-operative follow-up care. Fractures may be associated with significant outcomes due to the unplannable nature and reactionary care. The objective of this study was to determine if fractures were associated with an increased rate of short-term adverse health outcomes among children with CP, and if these associations were dependent on age.

Methods

This retrospective cohort study used commercial claims from 01/01/2001–12/31/2018. The primary cohort was children 2–18 years old with CP and an incident fracture (CP + Fx). Comparison cohorts were propensity score matched 1:1 to CP + Fx on demographic and health-related indicators: CP without fractures (CPw/oFx); without CP with (w/oCP + Fx) or without (w/oCPw/oFx) a fracture. The incidence rate (IR) and IR ratios (IRR) of 30-day and 31–90-day pneumonia and 90-day emergency department (ED) visit were estimated. Cox regression tested for effect modification by age and sex.

Results

The CP + Fx cohort (n = 1670) had higher IRs of 30-day pneumonia (IRR range, 1.53–4.54) and 90-day ED visit (IRR range, 1.45–2.37) (all P < 0.05), and higher IRs of 31–90-day pneumonia but this did not reach statistical significance (IRR, 1.41 to 2.32, all P > 0.05). Notably, there was evidence of effect modification by age. The rate of 30-day pneumonia became more problematic for CP + Fx with older age relative to comparison cohorts and for 90-day ED visit compared to CPw/oFx. The rate of 90-day ED visit for CP + Fx was more problematic at younger ages compared to w/oCP + Fx.

Conclusions

Fractures among children with CP were associated with an increased rate of short-term pneumonia and ED visit, which was more problematic with older age.

背景：脑瘫（CP）儿童骨折的风险很高；然而，人们对他们骨折后的健康状况却知之甚少。骨折是一种计划外事件，而手术或程序则有一个优化身体成分和健康的术前阶段以及有计划的术后随访护理。由于骨折的不可计划性和反应性护理，骨折可能会导致严重后果。本研究旨在确定骨折是否与 CP 儿童短期不良健康后果发生率的增加有关，以及这些关联是否与年龄有关：这项回顾性队列研究使用的是 2001 年 1 月 1 日至 2001 年 12 月 31 日期间的商业索赔。主要队列是 2-18 岁患有心绞痛并发生骨折（心绞痛 + 骨折）的儿童。对比队列在人口统计学和健康相关指标上与 CP + Fx 按 1:1 进行倾向评分匹配：无骨折的 CP（CPw/oFx）；无骨折的 CP（w/oCP + Fx）或无骨折的 CP（w/oCPw/oFx）。对 30 天和 31-90 天肺炎发病率（IR）和 90 天急诊就诊率（IRR）进行了估算。Cox回归检验了年龄和性别对影响的修饰作用：CP + Fx队列（n = 1670）的30天肺炎（IRR范围为1.53-4.54）和90天急诊就诊（IRR范围为1.45-2.37）的IRR较高（均为P 0.05）。值得注意的是，有证据表明年龄会影响效果。与 CPw/oFx 相比，年龄越大，CP + Fx 的 30 天肺炎发病率越高，90 天 ED 就诊率也越高。与CP/OFX相比，CP+Fx的90天急诊就诊率在年龄越小时问题越严重：结论：CP 儿童骨折与短期肺炎和急诊室就诊率增加有关，年龄越大，问题越严重。

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引用次数: 0

Phlpp1 alters the murine chondrocyte phospho-proteome during endochondral bone formation Phlpp1 在软骨内骨形成过程中改变了小鼠软骨细胞磷蛋白组。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-09-29 DOI: 10.1016/j.bone.2024.117265

Samantha R. Weaver , Eduardo Peralta-Herrera , Haydee M. Torres , Erik Jessen , Elizabeth W. Bradley , Jennifer J. Westendorf

Appendicular skeletal growth and bone mass acquisition are controlled by a variety of growth factors, hormones, and mechanical forces in a dynamic process called endochondral ossification. In long bones, chondrocytes in the growth plate proliferate and undergo hypertrophy to drive bone lengthening and mineralization. Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 and 2 (Phlpp1 and Phlpp2) are serine/threonine protein phosphatases that regulate cell proliferation, survival, and maturation via Akt, PKC, Raf1, S6k, and other intracellular signaling cascades. Germline deletion of Phlpp1 suppresses bone lengthening in growth plate chondrocytes. Here, we demonstrate that Phlpp2 does not regulate endochondral ossification, and we define the molecular differences between Phlpp1 and Phlpp2 in chondrocytes. Phlpp2^−/− mice were phenotypically indistinguishable from their wildtype (WT) littermates, with similar bone length, bone mass, and growth plate dynamics. Deletion of Phlpp2 had moderate effects on the chondrocyte transcriptome and proteome compared to WT cells. By contrast, Phlpp1/2^−/− (double knockout) mice resembled Phlpp1^−/− mice phenotypically and molecularly, as the chondrocyte phospho-proteomes of Phlpp1^−/− and Phlpp1/2^−/− chondrocytes had similarities and were significantly different from WT and Phlpp2^−/− chondrocyte phospho-proteomes. Data integration via multiparametric analysis showed that the transcriptome explained less variation in the data as a result of Phlpp1 or Phlpp2 deletion than proteome or phospho-proteome. Alterations in cell proliferation, collagen fibril organization, and Pdpk1 and Pak1/2 signaling pathways were identified in chondrocytes lacking Phlpp1, while cell cycle processes and Akt1 and Aurka signaling pathways were altered in chondrocytes lacking Phlpp2. These data demonstrate that Phlpp1, and to a lesser extent Phlpp2, regulate multiple and complex signaling cascades across the chondrocyte transcriptome, proteome, and phospho-proteome and that multi-omic data integration can reveal novel putative kinase targets that regulate endochondral ossification.

在一个称为软骨内骨化的动态过程中，各种生长因子、激素和机械力控制着骨骼的生长和骨量的获得。在长骨中，生长板中的软骨细胞增殖并发生肥大，从而推动骨骼的延长和矿化。Pleckstrin homology（PH）结构域和富亮氨酸重复磷酸酶 1 和 2（Phlpp1 和 Phlpp2）是丝氨酸/苏氨酸蛋白磷酸酶，可通过 Akt、PKC、Raf1、S6k 和其他细胞内信号级联调节细胞增殖、存活和成熟。基因缺失 Phlpp1 会抑制生长板软骨细胞的骨延长。在这里，我们证明了 Phlpp2 不调控软骨内骨化，并明确了 Phlpp1 和 Phlpp2 在软骨细胞中的分子差异。Phlpp2-/-小鼠在表型上与野生型（WT）小鼠无异，具有相似的骨长、骨量和生长板动力学。与 WT 细胞相比，Phlpp2 的缺失对软骨细胞转录组和蛋白质组的影响不大。相比之下，Phlpp1/2-/-（双基因敲除）小鼠在表型和分子上与Phlpp1-/-小鼠相似，因为Phlpp1-/-和Phlpp1/2-/-软骨细胞的软骨细胞磷酸蛋白组与WT和Phlpp2-/-软骨细胞磷酸蛋白组有相似之处和显著差异。通过多参数分析进行的数据整合显示，转录组对Phlpp1或Phlpp2缺失导致的数据变化的解释程度低于蛋白质组或磷酸化蛋白质组。在缺乏 Phlpp1 的软骨细胞中发现了细胞增殖、胶原纤维组织以及 Pdpk1 和 Pak1/2 信号通路的改变，而在缺乏 Phlpp2 的软骨细胞中发现了细胞周期过程以及 Akt1 和 Aurka 信号通路的改变。这些数据表明，Phlpp1（其次是 Phlpp2）可调控软骨细胞转录组、蛋白质组和磷酸化蛋白质组中多种复杂的信号级联，多组学数据整合可揭示调控软骨内骨化的新型推定激酶靶标。

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引用次数: 0

Lif-deficiency promote systemic Iron metabolism disorders and increases the susceptibility of osteoblasts to ferroptosis 缺乏 Lif 会导致全身性铁代谢紊乱，并增加成骨细胞对铁变态反应的易感性。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-09-26 DOI: 10.1016/j.bone.2024.117266

Yu Zhang , Yaqi Cong , Juan Du , Donghua Guo , Jing Huang , Junchen Pan , Youde Liang , Jiali Zhang , Zhou Ye , Yi Liu , Yi Zhou

Leukemia inhibitory factor (LIF) is a multifunctional cytokine that plays a crucial role in various biological processes. However, LIF involvement in iron metabolism remains almost unexplored. This study aimed to explore the impact of LIF on systemic iron transportation and its potential role in ferroptosis in osteoblasts. We observed that the Lif-deficient (Lif^−/−) mice is characterized by a reduction in bone mass and a decrease in bone mineral density compared with wild-type (WT) mice. Energy-dispersive X-ray spectroscopy revealed a marked increase in iron content on the surface of femurs from Lif^−/− mice. Meanwhile, iron stores test lower iron levels in the spleens and higher levels in the femurs of Lif^−/− mice. Besides, Lif^−/− mice display increased levels of serum iron, total iron-binding capacity, unsaturated iron-binding capacity, and transferrin saturation and serum ferritin relative to WT mice. Hepcidin mRNA expression reduction in the liver of Lif^−/− mice. It also holds true in the AML-12 hepatocyte cell line after Lif-knockdown. Immunohistochemistry and RT-PCR revealed elevated ferroportin (FPN) in duodenal cells of Lif^−/− mice. Lif-deficiency decreases SLC7A11 levels in osteoblasts. In addition, overexpression of LIF downregulates CD71, DCYTB, and DMT1, thereby reducing iron uptake in iron-overloaded cells. Femur immunohistochemistry (IHC) revealed increased ACSL4 and decreased GPX4 and SLC7A11, indicating an increase in ferroptosis of osteoblasts in Lif^−/− mice. Whole-transcriptome sequencing showed gene expression changes after Lif-knockdown, exhibiting a negative correlation with genes involved in long-chain fatty acid transport, mitochondrial organization, and the p38 MAPK signaling pathway. These results demonstrate that Lif-deficiency alter systemic iron metabolism and increases the susceptibility of osteoblasts to ferroptosis.

白血病抑制因子（LIF）是一种多功能细胞因子，在各种生物过程中发挥着至关重要的作用。然而，LIF 在铁代谢中的参与几乎仍未被探索。本研究旨在探讨 LIF 对全身铁运输的影响及其在成骨细胞铁变态反应中的潜在作用。我们观察到，与野生型（WT）小鼠相比，Lif 缺陷（Lif-/-）小鼠的特点是骨量减少和骨矿物质密度降低。能量色散 X 射线光谱显示，Lif-/- 小鼠股骨表面的铁含量明显增加。同时，铁储存测试显示，Lif-/-小鼠脾脏中的铁含量较低，而股骨中的铁含量较高。此外，与 WT 小鼠相比，Lif-/- 小鼠的血清铁、总铁结合力、不饱和铁结合力、转铁蛋白饱和度和血清铁蛋白水平均有所提高。Lif-/- 小鼠肝脏中的 Hepcidin mRNA 表达减少。Lif-基因敲除后，AML-12 肝细胞系中的情况也是如此。免疫组化和 RT-PCR 发现 Lif-/- 小鼠十二指肠细胞中的铁蛋白（FPN）升高。Lif缺陷会降低成骨细胞中SLC7A11的水平。此外，过表达 LIF 会下调 CD71、DCYTB 和 DMT1，从而减少铁过载细胞对铁的吸收。股骨免疫组化（IHC）显示，ACSL4增加，GPX4和SLC7A11减少，表明Lif-/-小鼠成骨细胞的铁变态反应增加。全转录组测序显示，Lif-基因敲除后基因表达发生变化，与涉及长链脂肪酸转运、线粒体组织和 p38 MAPK 信号通路的基因呈负相关。这些结果表明，Lif 缺失会改变全身铁代谢，并增加成骨细胞对铁变态反应的易感性。

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引用次数: 0

The independent and joint association between physical activity, sleep duration and daily sitting time with bone mineral density: A real world study from NHANES 2007–2018. 体育锻炼、睡眠时间和每天坐着的时间与骨矿物质密度之间的独立和联合关系：一项来自 2007-2018 年国家健康调查（NHANES）的真实世界研究。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-09-25 DOI: 10.1016/j.bone.2024.117264

Hongjiang Yang , Bo Li , Hailiang Li , Mi Zhou , Baicao Li , Junrui Guo , Hao Zhong , Song Liu , Qi Zhang , Cong Xing , Guangzhi Ning

Purpose

To assess the independent and joint effect of physical activity, sleep duration, and daily sitting time on bone mineral density (BMD), based on National Health and Nutrition Examination Survey (NHANES) 2007–2018.

Design

Cross-sectional design.

Methods

The primary outcome was risk of low BMD. All associations between lifestyle factors and the prevalence of low BMD were based on logistic regression, and dose-response relationships were further explored by restricted cubic spline (RCS). Finally, multiplicative and additive interaction was examined by P _interaction and relative excess risk due to interaction (RERI).

Results

10,346 individuals (N _{normal BMD} = 6353; N _{Low BMD} = 3993) were analyzed. Multivariate logistic regression indicated low intensity physical activity (odds ratio [OR] 0.84; 95 % confidence interval [95%CI] 0.78–0.90) and high intensity physical activity (0.67, 0.56–0.78) had protective impact on risk of low BMD, whereas short sleep (1.41, 1.20–1.64), long sleep (1.36, 1.03–1.79) and prolonged daily sitting (1.58, 1.32–1.88) had harmful effect. RCS revealed dose-response associations between physical activity (J-shaped), sleep duration (U-shaped), daily sitting time (positive-associated) and risk of low BMD. Multiplicative interaction between sleep duration and physical activity was observed (P _interaction = 0.003), while not between daily sitting time and physical activity (P _interaction = 0.600). Notably, negative additive interactions indicated that physical activity mitigated the increased risk of low BMD associated with irregular sleep patterns and prolonged sedentary behavior.

Conclusion

Increasing physical activity was presented as a modulating factor, potentially altering the relationship between independent variables that have deleterious effects on BMD like sleep duration and sedentary behavior. The study underscores the importance of lifestyle modifications in the prevention of early onset low BMD.

目的：根据2007-2018年美国国家健康与营养调查（NHANES），评估体力活动、睡眠时间和每日坐姿时间对骨矿物质密度（BMD）的独立和联合影响：设计：横断面设计：主要结果是低 BMD 风险。生活方式因素与低 BMD 患病率之间的所有关联均基于逻辑回归，剂量-反应关系则通过受限立方样条曲线（RCS）进一步探讨。最后，通过P交互作用和交互作用导致的相对超额风险（RERI）检验了乘法和加法交互作用：分析了 10346 人（正常 BMD = 6353 人；低 BMD = 3993 人）。多变量逻辑回归显示，低强度体力活动（几率比 [OR] 0.84；95% 置信区间 [95%CI] 0.78-0.90）和高强度体力活动（0.67，0.56-0.78）对低 BMD 风险具有保护作用，而短睡眠（1.41，1.20-1.64）、长睡眠（1.36，1.03-1.79）和每天久坐（1.58，1.32-1.88）则具有有害作用。RCS显示，体力活动（J形）、睡眠时间（U形）、每日久坐时间（正相关）与低BMD风险之间存在剂量-反应关系。睡眠时间与体力活动之间存在乘法交互作用（P 交互作用 = 0.003），而每日久坐时间与体力活动之间不存在乘法交互作用（P 交互作用 = 0.600）。值得注意的是，负相加相互作用表明，体育锻炼可减轻与不规律睡眠模式和长期久坐行为相关的低 BMD 风险的增加：增加体育锻炼是一个调节因素，有可能改变睡眠时间和久坐行为等对 BMD 有不利影响的自变量之间的关系。这项研究强调了改变生活方式对预防早发低 BMD 的重要性。

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