IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-01-04 DOI: 10.1016/j.bone.2024.117388

Meret Keiser , Stefan Preiss , Stephen J. Ferguson , Vincent A. Stadelmann

Osteoarthritis (OA) is associated with sclerosis, a thickening of the subchondral bone plate, yet little is known about bone adaptations around full-thickness cartilage defects in severe knee OA, particularly beneath bone-on-bone wear grooves. This high-resolution micro-computed tomography (microCT) study aimed to quantify subchondral bone microstructure relative to cartilage defect location, distance from the joint space, and groove depth.

Ten tibial plateaus with full-thickness cartilage defects were microCT-scanned to determine defect location and size. Wear groove depth was estimated as the thickness from its deepest point to a surface interpolated from the defect edges. Two 5 × 5 mm specimens were sampled from three regions (defect, edge, and cartilage-covered areas) and two from the contralateral condyle, then scanned at higher resolution. Bone density profiles were analyzed as a function of distance from the joint space to identify cortical and trabecular regions of interest and and compute their respective bone density and microstructure.

Cortical bone beneath defects was four times thicker under wear grooves than beneath cartilage. Bone density profiles significantly differed between the three specimen types at depths up to 5 mm. Below defects, cortical porosity was 85 % higher, and trabecular density 14 % higher, than in cartilage-covered specimens. Some trabecular spaces were filled with woven bone-like tissue, forming a new cortical layer. These changes were confined to the defect region and ceased abruptly at the defect edge. No correlation was found between bone microstructural indices and the estimated groove depth.

Our findings suggest an ongoing migration of the cortical layer during formation of the groove from its original position into the underlying trabecular bone, a process we termed “trabecular corticalization.” Under deeper wear grooves, the new cortical layer exhibited large pores connecting bone marrow to the joint space, suggesting physiological limits to corticalization. These results highlight specific bone adaptations beneath cartilage defects in severe OA and provide insights into the progression of subchondral bone changes under bone-on-bone contact areas.

骨关节炎（OA）与硬化症（软骨下骨板增厚）有关，但对严重膝关节OA患者全层软骨缺损周围的骨适应知之甚少，特别是骨对骨磨损槽下的骨适应。这项高分辨率微计算机断层扫描（microCT）研究旨在量化软骨下骨微观结构与软骨缺损位置、关节间隙距离和凹槽深度的关系。对10例全层软骨缺损的胫骨平台进行显微ct扫描以确定缺损的位置和大小。磨损槽深度估计为从其最深点到从缺陷边缘插值的表面的厚度。分别从三个区域（缺损区、边缘区和软骨覆盖区）和对侧髁上取样2个5 × 5 mm标本，然后进行高分辨率扫描。骨密度曲线作为距离关节空间的函数进行分析，以识别感兴趣的皮质和小梁区域，并计算它们各自的骨密度和微观结构。缺损下皮质骨在磨损沟下的厚度是软骨下的4倍。在深度达5毫米处，三种标本类型的骨密度分布显著不同。缺损以下，皮质孔隙率比软骨覆盖标本高85%，小梁密度高14%。一些骨小梁间隙被编织的骨样组织填充，形成新的皮质层。这些变化局限于缺陷区域，并在缺陷边缘突然停止。骨显微结构指标与估计的骨沟深度之间没有相关性。我们的研究结果表明，在沟的形成过程中，皮质层从其原始位置持续迁移到下面的小梁骨，这一过程我们称之为“小梁皮质化”。在更深的磨损槽下，新的皮质层显示出连接骨髓和关节间隙的大孔隙，表明皮质化的生理限制。这些结果突出了严重骨关节炎软骨缺损下的特定骨适应，并为骨与骨接触区域下软骨下骨变化的进展提供了见解。

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引用次数: 0

Multiscale interstitial fluid computation modeling of cortical bone to characterize the hydromechanical stimulation of lacunar-canalicular network 皮质骨的多尺度间质流体计算模型表征腔隙网络的水力学刺激。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-31 DOI: 10.1016/j.bone.2024.117386

WeiLun Yu , RenXia Ou , Qi Hou , ChunMing Li , XiaoHang Yang , YingHui Ma , XiaoGang Wu , WeiYi Chen

Bone tissue is a biological composite material with a complex hierarchical structure that could continuously adjust its internal structure to adapt to the alterations in the external load environment. The fluid flow within bone is the main route of osteocyte metabolism, and the pore pressure as well as the fluid shear stress generated by it are important mechanical stimuli perceived by osteocytes. Owing to the irregular multiscale structure of bone tissue, the fluid stimulation that lacunar-canalicular network (LCN) in different regions of the tissue underwent remained unclear. In this study, we constructed a multiscale conduction model of fluid flow stimulus signals in bone tissue based on the poroelasticity theory. We analyzed the fluid flow behaviors at the macro-scale (whole bone tissue), macro-meso scale (periosteum, interstitial bone, osteon and endosteum), and micro-scale (lacunar-osteocyte-canalicular) levels. We explored how fluid stimulation at the tissue level correlated with that at the cellular level in cortical bone and characterized the distributions of the pore pressure, fluid velocity and fluid shear stress that the osteocytes experienced across the entire tissue structure. The results showed that the initial conditions of intramedullary pressure had a significant impact on the pore pressure of Haversian systems, but had a relatively small influence on the fluid velocity. The osteocyte which were located at different positions in the bone tissue received very distinct fluid stimuli. Osteocytes in the vicinity of the Haversian Canals experienced higher fluid shear stress stimulation. When the permeability of the LCN was within the range from 10⁻²¹ m² to 10⁻¹⁸ m², the distribution of pressure, fluid velocity and fluid shear stress within the osteon near the periosteum and endosteum was significantly different from that in other parts of the bone. However, when the permeability was less than 10⁻²² m², such a difference did not exist. Particularly, the flow velocity at the lacunae was markedly higher than that in the canaliculi. Meanwhile, the pore pressure and fluid shear stress were conspicuously lower than those in the canaliculi. In this study, we considered the interconnections of different biofunctional units at different scales of bone tissue, construct a more complete multiscale model of bone tissue, and propose that osteocytes at different locations receive different fluid stimuli, which provides a reference for a deeper understanding of bone mechanotransduction.

骨组织是一种具有复杂层次结构的生物复合材料，能够不断调整其内部结构以适应外部载荷环境的变化。骨内流体流动是骨细胞代谢的主要途径，其产生的孔隙压力和流体剪切应力是骨细胞感知的重要机械刺激。由于骨组织的不规则多尺度结构，组织不同区域的腔隙-小管网络（LCN）所受的液体刺激尚不清楚。在本研究中，我们基于孔隙弹性理论构建了骨组织中流体流动刺激信号的多尺度传导模型。我们分析了宏观尺度（整个骨组织）、宏观中观尺度（骨膜、骨间质、骨细胞和骨内膜）和微观尺度（腔隙-骨细胞-骨管）水平上的流体流动行为。我们探索了皮质骨中组织水平的流体刺激与细胞水平的流体刺激之间的相关性，并表征了骨细胞在整个组织结构中所经历的孔隙压力、流体速度和流体剪切应力的分布。结果表明：初始压力条件对Haversian体系孔隙压力有显著影响，但对流体速度的影响相对较小；位于骨组织中不同位置的骨细胞受到非常不同的液体刺激。哈弗氏管附近的骨细胞经历了更高的流体剪切应力刺激。当LCN通透性在10-21 - m2 ~ 10-18 - m2范围内时，骨膜和内膜附近骨内的压力、流体速度和流体剪切应力分布与骨其他部位有显著差异。而当渗透率小于10-22 m2时，则不存在这种差异。特别是腔隙处的流速明显高于小管。同时，孔隙压力和流体剪应力明显低于小管。在本研究中，我们考虑了骨组织不同尺度上不同生物功能单元的相互联系，构建了更完整的骨组织多尺度模型，并提出不同位置的骨细胞接受不同的流体刺激，为更深入地理解骨力学转导提供了参考。

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引用次数: 0

Obesity and insulinopenic type 2 diabetes differentially impact, bone phenotype, bone marrow adipose tissue, and serum levels of the cathelicidin-related antimicrobial peptide in mice 肥胖和胰岛素缺乏型2型糖尿病对小鼠骨骼表型、骨髓脂肪组织和血清抗菌肽水平的差异影响

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-30 DOI: 10.1016/j.bone.2024.117387

Amélie Paquet , Nadia Bahlouli , Xavier Coutel , Damien Leterme , Jérôme Delattre , Véronique Gauthier , Flore Miellot , Séverine Delplace , Hélène Rouge-Labriet , Nicolas Bertheaume , Christophe Chauveau , Hamanou Benachour

Obesity is a risk factor of developing type 2 diabetes (T2D) and metabolic complications, through systemic inflammation and insulin resistance. It has also been associated with increased bone marrow adipocytes along with increased bone fragility and fracture risk. However, the differential effects of obesity and T2D on bone fragility remain unclear. The cathelicidin-related antimicrobial peptide (CRAMP) is a multifunctional modulator of the innate immunity that has emerged as biomarker of cardiometabolic diseases. The aims of this study were i) to assess the differential impact between hyperinsulinemic obesity versus insulinopenic T2D, on bone phenotype and bone marrow adipose tissue (BMAT), and ii) to analyse the link with CRAMP expression and its circulating levels in the context of obesity and T2D. We used C57BL/6 J male mice models of obesity induced by high-fat diet (HFD), and of insulinopenic T2D induced by streptozotocin (STZ) treatment combined with HFD, reflecting the metabolic heterogeneity of the diseases. As compared to low-fat diet (LFD) control group after 16 weeks of feeding, the HFD mice exhibit a significant weight gain, moderate hyperglycaemia, impaired glucose tolerance and insulin sensitivity, and significant increase in serum insulin levels. This hyperinsulinemic obesity led to decreased trabecular (Tb.Th) and cortical thickness (Ct.Th) in the tibia, associated with significant BMAT expansion, in addition to increased subcutaneaous (SCAT) and visceral adipose tissue (VAT). No changes were observed in the circulating levels of CRAMP peptide neither in other bone parameters. While, STZ treatment in HFD/STZ group induced a more severe hyperglycaemia, glucose intolerance and insulin resistance, and hypoinsulinemia. We also observed a negative effect on the expansion of both SCAT and VAT, as well as lower increase in BMAT as compared to HFD group. However, these mice with insulinopenic T2D exhibit early decrease in trabecular number (Tb.N) in proximal tibia, progressively from 8 to 16 weeks of protocol, and impaired femoral biomechanical stiffness. These alterations are also accompanied with decreased circulating levels of the CRAMP peptide in the HFD/STZ mice. The CRAMP mRNA levels decreased in VAT of both HFD and HFD/STZ groups.

Overall, these results provide novel insights into the differential negative impact of obesity versus T2D on bone microenvironment, and suggest a link between hyperglycaemia-induced bone quality alterations during insulinopenia, and impaired regulation of the cathelicidin peptide of the innate immunity. Further investigations are needed to elucidate this relationship.

肥胖是发生2型糖尿病（T2D）和代谢并发症的危险因素，通过全身性炎症和胰岛素抵抗。它还与骨髓脂肪细胞增加以及骨骼脆性和骨折风险增加有关。然而，肥胖和T2D对骨骼脆性的不同影响尚不清楚。抗菌肽相关抗菌肽（CRAMP）是先天免疫的多功能调节剂，已成为心脏代谢疾病的生物标志物。本研究的目的是1)评估高胰岛素血症型肥胖与胰岛素缺乏型T2D对骨骼表型和骨髓脂肪组织（BMAT）的差异影响，以及2)分析肥胖和T2D背景下与抽筋表达及其循环水平的联系。我们采用C57BL/6 J雄性小鼠高脂饮食（HFD）诱导的肥胖模型，以及链脲佐菌素（STZ）联合HFD诱导的胰岛素缺乏型T2D模型，反映了两种疾病的代谢异质性。与低脂饮食（LFD）对照组相比，喂食16 周后，HFD小鼠表现出明显的体重增加，中度高血糖，糖耐量和胰岛素敏感性受损，血清胰岛素水平显著升高。这种高胰岛素性肥胖导致胫骨小梁（Tb.Th）和皮质厚度（Ct.Th）减少，除了皮下（SCAT）和内脏脂肪组织（VAT）增加外，还伴有显著的BMAT扩张。在循环中没有观察到痉挛肽水平的变化，也没有观察到其他骨骼参数的变化。而HFD/STZ组的高血糖、葡萄糖耐受不良、胰岛素抵抗和低胰岛素血症更为严重。我们还观察到，与HFD组相比，SCAT和VAT的扩张受到负面影响，BMAT的增长也较低。然而，这些胰岛素缺乏T2D的小鼠表现出胫骨近端小梁数量（Tb.N）的早期减少，从8到16 周逐渐减少，并且股骨生物力学刚度受损。这些改变还伴随着HFD/STZ小鼠循环中抽筋肽水平的降低。HFD组和HFD/STZ组VAT中CRAMP mRNA水平均降低。总的来说，这些结果为肥胖和T2D对骨微环境的不同负面影响提供了新的见解，并表明胰岛素缺乏期间高血糖诱导的骨质量改变与先天免疫的抗菌肽调节受损之间存在联系。需要进一步的研究来阐明这种关系。

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引用次数: 0

Primary components of MCT ketogenic diet are detrimental to bone loss associated with accelerated aging and age-related neurotoxicity in mice MCT生酮饮食的主要成分是有害的骨质流失与加速衰老和年龄相关的神经毒性小鼠。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-26 DOI: 10.1016/j.bone.2024.117383

Shreshta Jain, Divya Vohora

Medium chained triglycerides (MCT) ketogenic diet is being extensively investigated for its neuroprotective effects against adverse effects associated with aging and neurodegenerative disorders. Aging is a common risk factor for the development of both osteoporosis and neurological disorders. Hence, suppression of aging and age-related neurodegeneration might contribute to delaying skeletal aging. The present study was designed to investigate the effects of the primary components of the MCT diet, against bone resorption associated with D-gal-induced accelerated aging and D-gal /AlCl₃-induced age-related toxicity. We report bone loss in accelerated aged mice and age-related neurotoxic mice through declined Sirtuin1 (SIRT1) expression, depleted bone turnover markers, (P1NP and β-CTX-1), low bone mineral density (BMD), and deterioration of trabecular bone microarchitecture in both the distal femur and proximal tibia bones. Administration of MCT dietary components decanoic acid and octanoic acid, led to a decrease in body weight and only octanoic acid increased serum levels of ketone body, β-hydroxybutyrate (β-HB), but both of them failed to reverse the diminishing effects on bone health associated with aging and age-related neurotoxicity. Surprisingly, decanoic acid, octanoic acid, and their combination also exhibited negative effects on trabecular bone microarchitecture and BMD in the distal femur and proximal tibia bones of healthy mice. The findings from this study provide supporting evidence on the deterioration of bone health associated with aging and age-related neurotoxicity, and the bone resorption potential of MCT dietary supplements that are being prescribed in healthy older populations and elderly persons diagnosed with neurological disorders.

中链甘油三酯（MCT）生酮饮食因其对衰老和神经退行性疾病相关不良反应的神经保护作用而被广泛研究。衰老是骨质疏松症和神经系统疾病发展的常见危险因素。因此，抑制衰老和与年龄相关的神经变性可能有助于延缓骨骼老化。本研究旨在研究MCT饮食的主要成分对与D-gal诱导的加速衰老和D-gal / alcl3诱导的年龄相关毒性相关的骨吸收的影响。我们报道了加速衰老小鼠和与年龄相关的神经毒性小鼠的骨质流失，表现为Sirtuin1 （SIRT1）表达下降、骨转换标志物（P1NP和β-CTX-1）减少、骨密度（BMD）降低以及股骨远端和胫骨近端骨小梁微结构恶化。服用MCT膳食成分癸酸和辛酸导致体重下降，只有辛酸增加了酮体β-羟基丁酸（β-HB）的血清水平，但两者都未能逆转与衰老和年龄相关的神经毒性相关的骨骼健康减弱效应。令人惊讶的是，癸酸、辛酸及其组合对健康小鼠股骨远端和胫骨近端骨的骨小梁微结构和骨密度也有负面影响。这项研究的结果为骨质健康恶化与衰老和与年龄相关的神经毒性相关以及MCT膳食补充剂的骨吸收潜力提供了支持性证据，MCT膳食补充剂被开具给健康的老年人和被诊断患有神经系统疾病的老年人。

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引用次数: 0

PTX3-assembled pericellular hyaluronan matrix enhances endochondral ossification during fracture healing and heterotopic ossification ptx3组装的细胞周围透明质酸基质在骨折愈合和异位骨化过程中增强软骨内骨化。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-26 DOI: 10.1016/j.bone.2024.117385

Wei Dong, Chang Yang, Donghua Guo, Meie Jia, Yan Wang, Jiawei Wang

Endochondral ossification (EO) is a pivotal process during fracture healing and traumatic heterotopic ossification (HO), involving the cartilaginous matrix synthesis and mineralization. Unlike the extracellular matrix, the hyaluronan (HA)-rich pericellular matrix (PCM) directly envelops chondrocytes, serving as the frontline for extracellular signal reception and undergoing dynamic remodeling. Pentraxin 3 (PTX3), a secreted glycoprotein, facilitates HA matrix assembly and remodeling. However, it remains unclear whether PTX3 affects EO by regulating HA-rich PCM assembly of chondrocytes, thereby impacting fracture healing and traumatic HO. This study demonstrates that PTX3 deficiency impairs fracture healing and inhibits traumatic HO, but dose not affect growth plate development in mice. PTX3 expression is up-regulated during chondrocyte matrix synthesis and maturation and is localized in the HA-rich PCM. PTX3 promotes the assembly of HA-rich PCM in a serum- and TSG6-dependent manner, fostering CD44 receptor clustering, activating the FAK/AKT signaling pathway, and promoting chondrocyte matrix synthesis and maturation. Local injection of PTX3/TSG6 matrix protein mixture effectively promotes fracture healing in mice. In conclusion, PTX3-assembled HA-rich PCM promotes chondrocyte matrix synthesis and maturation via CD44/FAK/AKT signaling. This mechanism facilitates EO during fracture healing and traumatic HO in mice.

软骨内成骨（EO）是骨折愈合和外伤性异位骨化（HO）的关键过程，涉及软骨基质的合成和矿化。与细胞外基质不同，富含透明质酸（HA）的细胞外基质（PCM）直接包裹软骨细胞，作为细胞外信号接收的前线并进行动态重塑。penttraxin 3 （PTX3）是一种分泌的糖蛋白，促进HA基质的组装和重塑。然而，目前尚不清楚PTX3是否通过调节软骨细胞中富含ha的PCM组装来影响EO，从而影响骨折愈合和外伤性HO。本研究表明，PTX3缺乏会损害骨折愈合并抑制创伤性HO，但不影响小鼠生长板的发育。PTX3在软骨细胞基质合成和成熟过程中表达上调，并定位于富含ha的PCM。PTX3以依赖血清和tsg -6的方式促进富含ha的PCM的组装，促进CD44受体聚集，激活FAK/AKT信号通路，促进软骨细胞基质的合成和成熟。局部注射PTX3/TSG-6基质蛋白混合物可有效促进小鼠骨折愈合。综上所述，ptx3组装的富含ha的PCM通过CD44/FAK/AKT信号通路促进软骨细胞基质的合成和成熟。这一机制促进了小鼠骨折愈合和创伤性HO过程中的EO。

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引用次数: 0

NRF2-mediated osteoblast anti-ferroptosis effect promotes induced membrane osteogenesis nrf2介导的成骨细胞抗铁下垂作用促进诱导膜成骨。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-26 DOI: 10.1016/j.bone.2024.117384

Shuyuan Li , Shuying Li , Dawen Yang , Jingtao Zhang , Songyang Wang , Zhanpeng Zeng , Qunbin Cai , Qishi Zhou

Induced membrane technique (IMT) is a new method for repairing segmental bone defects. However, the mechanism of its defect repair is not clear. In recent years, several studies have gradually indicated that ferroptosis is closely related to bone remodeling. Therefore, this study mainly explored the impact of NRF2-mediated osteoblast anti-ferroptosis on bone mineralization within the induced membrane. Male Sprague-Dawley rats aged 12–14 weeks were randomly divided into four groups (n = 12): Model group, DMF (NRF2 agonist) group, ML385 (NRF2 inhibitor) group and Sham group. Except for Sham group, an IMT model of the right femur was established in all other groups. After 4 weeks and 8 weeks of treatment with DMF and ML385, compared to Model group, DMF group showed significantly higher levels of bone volume fraction (BV/TV), osteogenic factors and NRF2/ARE pathway-related factors (NRF2, GPX4, HO-1 and SLC7A11), while ferroptosis-related indicators (total iron, 4-HNE and MDA) were significantly lower. Conversely, ML385 group exhibited significantly higher ferroptosis-related indicators and lower levels of NRF2/ARE pathway-related factors and osteogenesis. In vitro, erastin could induce ferroptosis in osteoblasts. Compared to Erastin group, Erastin+oe-NRF2 (NRF2 overexpression) group showed significantly increased cell viability, mineralization ability, and levels of NRF2/ARE pathway-related factors, along with reduced ferroptosis effects. However, Erastin+si-NRF2 (NRF2 small interfering) group displayed enhanced ferroptosis effects and significantly reduced cell viability, mineralization ability, and levels of NRF2/ARE pathway-related factors. In conclusion, in the bone grafting area of the induced membrane, there existed ferroptosis caused by iron overload. Activating the anti-ferroptosis effect of osteoblasts mediated by the NRF2/ARE signaling cascade could promote growth and mineralization of bone grafts within the induced membrane.

诱导膜技术（IMT）是修复骨缺损的一种新方法。然而，其缺陷修复机制尚不清楚。近年来，一些研究逐渐表明，铁下垂与骨重塑密切相关。因此，本研究主要探讨nrf2介导的成骨细胞抗铁下沉对诱导膜内骨矿化的影响。将12 ~ 14 周龄雄性sd大鼠随机分为4组（n = 12）：模型组、DMF （NRF2激动剂）组、ML385 （NRF2抑制剂）组和Sham组。除Sham组外，其余各组均建立右股骨IMT模型。DMF和ML385治疗4 周和8 周后，与模型组比较，DMF组大鼠骨体积分数（BV/TV）、成骨因子及NRF2/ARE通路相关因子（NRF2、GPX4、HO-1、SLC7A11）水平均显著升高，而凋亡相关指标（总铁、4- hne、MDA）水平均显著降低。相反，ML385组的铁中毒相关指标明显升高，NRF2/ARE通路相关因子和成骨作用水平明显降低。在体外，erastin可诱导成骨细胞铁下垂。与Erastin组相比，Erastin+ e-NRF2 （NRF2过表达）组的细胞活力、矿化能力和NRF2/ARE通路相关因子水平均显著提高，铁沉效应降低。然而，Erastin+si-NRF2 （NRF2小干扰）组表现出增强的铁凋亡作用，显著降低细胞活力、矿化能力和NRF2/ARE通路相关因子的水平。综上所述，在诱导膜的植骨区存在铁超载引起的铁下垂。激活NRF2/ARE信号级联介导的成骨细胞抗铁下沉作用，可促进诱导膜内骨移植物的生长和矿化。

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引用次数: 0

Metabolism-epigenetic interaction-based bone and dental regeneration: From impacts and mechanisms to treatment potential 基于代谢-表观遗传相互作用的骨和牙再生：从影响和机制到治疗潜力。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-25 DOI: 10.1016/j.bone.2024.117382

Xinyi Chen , Xiaoyuan Huang , Xiatong Zhang, Zhuo Chen

Metabolic pathways exhibit fluctuating activities during bone and dental loss and defects, suggesting a regulated metabolic plasticity. Skeletal remodeling is an energy-demanding process related to altered metabolic activities. These metabolic changes are frequently associated with epigenetic modifications, including variations in the expression or activity of enzymes modified through epigenetic mechanisms, which directly or indirectly impact cellular metabolism. Metabolic reprogramming driven by bone and dental conditions alters the epigenetic landscape by modulating the activities of DNA and histone modification enzymes at the metabolite level. Epigenetic mechanisms modulate the expression of metabolic genes, consequently influencing the metabolome. The interplay between epigenetics and metabolomics is crucial in maintaining bone and dental homeostasis by preserving cell proliferation and pluripotency. This review, therefore, aims to examine the effects of metabolic reprogramming in bone and dental-related cells on the regulation of epigenetic modifications, particularly acetylation, methylation, and lactylation. We also discuss the effects of chromatin-modifying enzymes on metabolism and the potential therapeutic benefits of dietary compounds as epigenetic modulators. In this review, we highlight the inconsistencies in current research findings and suggest potential approaches to translate fundamental insights into clinical treatments for bone and tooth diseases.

在骨和牙齿丢失和缺损期间，代谢途径表现出波动的活动，表明代谢可塑性受到调节。骨骼重塑是一个与代谢活动改变有关的能量消耗过程。这些代谢变化通常与表观遗传修饰有关，包括通过表观遗传机制修饰的酶的表达或活性的变化，这些变化直接或间接地影响细胞代谢。由骨骼和牙齿状况驱动的代谢重编程通过在代谢物水平上调节DNA和组蛋白修饰酶的活性来改变表观遗传景观。表观遗传机制调节代谢基因的表达，从而影响代谢组。表观遗传学和代谢组学之间的相互作用对于通过保持细胞增殖和多能性来维持骨和牙齿的稳态至关重要。因此，本综述旨在研究骨和牙齿相关细胞代谢重编程对表观遗传修饰调控的影响，特别是乙酰化、甲基化和乳酸化。我们还讨论了染色质修饰酶对代谢的影响以及膳食化合物作为表观遗传调节剂的潜在治疗益处。在这篇综述中，我们强调了目前研究结果的不一致之处，并提出了将基本见解转化为骨和牙齿疾病临床治疗的潜在方法。

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引用次数: 0

Exogenous bone sialoprotein improves extraction socket healing in Ibsp knockout and wild-type mice 外源性骨唾液蛋白促进ibsp敲除小鼠和野生型小鼠拔牙窝愈合。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-23 DOI: 10.1016/j.bone.2024.117381

M.B. Chavez , N.L. Andras , M.H. Tan , T.N. Kolli , E.Y. Chu , H.A. Goldberg , B.L. Foster

Bone sialoprotein (Ibsp/BSP) is a bone-associated extracellular matrix protein. Ibsp knockout (Ibsp^−/−) mice exhibit defective alveolar bone formation, mineralization, and healing. We hypothesized BSP would rescue defective alveolar bone healing in a molar extraction model in Ibsp^−/− mice. Collagen gel with or without native rat BSP (nBSP) or recombinant rat BSP (rBSP) was delivered to sockets after first maxillary molar extraction in Ibsp^−/− and wild-type (WT) mice. Tissues were harvested 0, 1, 2, 7, and 14 days post-procedure (dpp) and analyzed by micro-computed tomography, histology, and immunohistochemistry (IHC). Histology and IHC demonstrated that collagen and BSP were retained within sockets. At 14 dpp, both bone volume fraction (BV/TV) and bone mineral density (BMD) were increased by both nBSP (over 50 %) and rBSP (over 60 %), compared to collagen alone in Ibsp^−/− mice. In WT alveolar bone, BV/TV and BMD were also increased by nBSP (over 30 %) and rBSP (over 60 %) compared to collagen controls. Gene expression analyses revealed few changes from delivery of nBSP, while addition of rBSP resulted in regulation of cell signaling, ECM, mineralization, and osteoblast/osteoclast-associated genes. Exogenous BSP rescued alveolar bone healing defects in Ibsp^−/− mice and enhanced bone healing in WT mice. Despite both forms of BSP improving bone healing, the substantial differences in how they regulate gene expression suggests that exogenous BSP acts in a complex, multifunctional manner to promote bone healing. These results support BSP as a novel approach to improve the quantity and quality of new bone in socket healing.

骨唾液蛋白（Ibsp/BSP）是骨相关的细胞外基质蛋白。Ibsp基因敲除（Ibsp-/-）小鼠表现出牙槽骨形成、矿化和愈合缺陷。我们假设BSP可以修复Ibsp-/-小鼠磨牙拔牙模型中有缺陷的牙槽骨愈合。将含或不含天然大鼠BSP （nBSP）或重组大鼠BSP （rBSP）的胶原凝胶在Ibsp-/-和野生型（WT）小鼠第一次上颌磨牙拔牙后送到牙槽中。分别于术后（dpp） 0、1、2、7和14 天采集组织，并通过显微计算机断层扫描、组织学和免疫组织化学（IHC）进行分析。组织学和免疫组化显示胶原蛋白和BSP保留在窝内。在14 dpp时，与单独的Ibsp-/-小鼠相比，nBSP（超过50 %）和rBSP（超过60 %）均增加了骨体积分数（BV/TV）和骨矿物质密度（BMD）。在WT牙槽骨中，与胶原对照相比，nBSP（超过30 %）和rBSP（超过60 %）也增加了BV/TV和BMD。基因表达分析显示，nBSP的递送几乎没有改变，而rBSP的添加导致细胞信号传导、ECM、矿化和成骨细胞/破骨细胞相关基因的调节。外源性BSP修复了Ibsp-/-小鼠的牙槽骨愈合缺陷，并促进了WT小鼠的骨愈合。尽管两种形式的BSP都能促进骨愈合，但它们调节基因表达的方式存在实质性差异，这表明外源性BSP以复杂、多功能的方式促进骨愈合。这些结果支持BSP作为一种新的方法来提高新骨的数量和质量在窝愈合。

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引用次数: 0

Characterisation of the influence of dietary fat and sugar on bone health utilising densitometry, micro-computed tomography and histomorphometry 利用密度测量、显微计算机断层扫描和组织形态测量来表征膳食脂肪和糖对骨骼健康的影响。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-20 DOI: 10.1016/j.bone.2024.117380

J. Khan , H. Sadie-Van Gijsen , L.M. Kotzé-Hörstmann , S.H. Kotze , J.I. Layman-Lemphane

Obesogenic feeding can affect systemic metabolism and impact bone health and microarchitecture, but the findings of published studies often appear contradictory. This study aimed to compare the effects of a medium-fat/high-sugar (MF/HS) and a high-fat/high-fructose (HF/Fr) diet on the femora of weanling male Wistar rats, examining bone mineral content and density (BMC, BMD), cortical and cancellous bone microarchitecture and the cell populations within bone. Furthermore, we explored the correlations between circulating bone-targeting factors (in particular leptin, adiponectin and insulin) and bone parameters. Rats were assigned to one of three dietary groups (control: CON; MF/HS: OB1; HF/Fr: OB2; n = 12 each) for 17 weeks. Right-hand side femora were subjected to densitometry to measure BMC and BMD, and micro-computed tomography (μCT) was utilised to assess cortical and cancellous bone. Osteoblast (N.Ob), osteoclast (N.Oc), adipocyte (N.Ad) and chondrocyte numbers (N.Ch) were quantified histomorphometrically. Diet OB1 was largely beneficial to bone, while diet OB2 exerted detrimental effects on BMC, BMD, bone microarchitecture and bone cell populations. In cortical bone, N.Ob was positively correlated with BMD, cortical area and serum leptin. In cancellous bone, N.Ob was positively correlated with serum leptin and BMD, while N.Oc was negatively correlated with serum leptin. Overall, these findings support a role for endogenous circulating leptin in promoting bone formation. We conclude that the impact of different obesogenic diets may be driven by individual dietary effects on circulating factors, which may partly explain the contradictory reports in existing literature on the impact of HF and HS diets on bone.

致肥性喂养会影响全身代谢，影响骨骼健康和微结构，但已发表的研究结果往往自相矛盾。本研究旨在比较中脂肪/高糖（MF/HS）和高脂肪/高果糖（HF/Fr）饮食对断奶雄性Wistar大鼠股骨的影响，检测骨矿物质含量和密度（BMC、BMD）、皮质和松质骨微结构以及骨内细胞群。此外，我们探讨了循环骨靶向因子（特别是瘦素、脂联素和胰岛素）与骨参数之间的相关性。将大鼠分为三个饮食组(对照组：CON；MF / HS: OB1;高频/ Fr: OB2;N = 每个12)17 周。右侧股骨进行密度测量，测量BMC和BMD，微计算机断层扫描（μCT）评估皮质骨和松质骨。对成骨细胞（N.Ob）、破骨细胞（N.Oc）、脂肪细胞（N.Ad）和软骨细胞数量（N.Ch）进行组织形态学定量。饲粮OB1对骨骼有益，而饲粮OB2对BMC、骨密度、骨微结构和骨细胞群有不利影响。皮质骨N.Ob与骨密度、皮质面积、血清瘦素呈正相关。在松质骨中，N.Ob与血清瘦素、骨密度呈正相关，N.Oc与血清瘦素呈负相关。总的来说，这些发现支持内源性循环瘦素在促进骨形成中的作用。我们得出结论，不同的致肥饮食的影响可能是由个体饮食对循环因子的影响驱动的，这可能部分解释了现有文献中关于HF和HS饮食对骨骼影响的矛盾报道。

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引用次数: 0

HR-pQCT measurements of changes in periarticular bone density and microarchitecture one year after acute knee injury and after reconstructive surgery HR-pQCT测量急性膝关节损伤和重建手术后一年内关节周围骨密度和微结构的变化。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2024-12-20 DOI: 10.1016/j.bone.2024.117376

Nathan J. Neeteson , Annabel R. Bugbird , Callie Stirling , Nina Pavlovic , Sarah L. Manske , Richard E.A. Walker , Steven K. Boyd

ACL injuries commonly lead to post-traumatic osteoarthritis (PTOA), but the underlying mechanism is not well-understood. One theorized mechanism is pathological bone remodelling following an ACL tear, for which high-resolution peripheral quantitative computed tomography (HR-pQCT) is uniquely positioned to investigate in vivo in humans. In this study, we longitudinally investigate the one-year changes in periarticular bone density and microarchitecture in the human knee following an ACL tear and reconstructive surgery using data sampled from an on-going observational cohort study. We reduce the number of individual microarchitectural parameters using factor analysis and model one-year changes with mixed-effects models, adjusting for the effects of age, sex, meniscus status, and the baseline microarchitectural state. We find significant evidence of persistent bone density losses one year after both injury and surgery. We also observe significant increases in trabecular separation post-injury, indicating significant structural degradation, and significant increases in subchondral bone plate density post-surgery, a sign of early stiffening. Finally, we observe minimal significant contrasts for the effects of age, sex, and meniscus status, while we observe that the state of the microarchitecture at baseline has significant and varied effects on the subsequent changes, suggesting that the influence of PTOA risk factors on post-injury and post-surgery bone changes may be mediated through the state of the periarticular microarchitecture at injury and/or at surgery. In summary, we found that degradation of periarticular bone microarchitecture was observed post-injury, densification of the subchondral bone plate was observed post-surgery, and the state of the bone microarchitecture at baseline may mediate the influence of PTOA risk factors on post-injury microarchitectural adaptations.

前交叉韧带损伤通常导致创伤后骨关节炎（PTOA），但其潜在机制尚不清楚。一种理论机制是前交叉韧带撕裂后的病理性骨重塑，对此，高分辨率外周定量计算机断层扫描（HR-pQCT）具有独特的定位，可以在人体体内进行研究。在这项研究中，我们利用一项正在进行的观察性队列研究的数据，纵向调查了ACL撕裂和重建手术后人类膝关节关节周围骨密度和微结构在一年内的变化。我们使用因子分析减少个体微建筑参数的数量，并使用混合效应模型对一年的变化进行建模，调整年龄、性别、半月板状态和基线微建筑状态的影响。我们发现明显的证据表明，在受伤和手术后一年骨密度持续下降。我们还观察到损伤后小梁分离显著增加，表明明显的结构退化，术后软骨下骨板密度显著增加，这是早期硬化的迹象。最后，我们观察到年龄、性别和半月板状态的影响没有显著差异，但我们观察到基线时的微结构状态对随后的变化有显著和不同的影响，这表明PTOA危险因素对损伤后和术后骨变化的影响可能是通过损伤和/或手术时关节周围微结构的状态来调节的。综上所述，我们发现损伤后观察到关节周围骨微结构的退化，手术后观察到软骨下骨板的致密化，骨微结构在基线的状态可能介导了PTOA危险因素对损伤后微结构适应的影响。

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引用次数: 0

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