PDF(Pubmed)
Abstract：
Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156-0.366]) vs non-diabetic subjects 0.352% [0.269-0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46-30.10] vs non-diabetic subjects 76.24 MPa [26.81-132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=-0.7500, p=0.0255; r=-0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young\'s modulus was negatively correlated with SOST (r=-0.5675, p=0.0011), AXIN2 (r=-0.5523, p=0.0042), and SFRP5 (r=-0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.
Type 2 diabetes is a long-term metabolic disease characterised by chronic high blood sugar levels. This in turn has a negative impact on the health of other tissues and organs, including bones. Type 2 diabetes patients have an increased risk of fracturing bones compared to non-diabetics. This is particularly true for fragility fractures, which are fractures caused by falls from a short height (i.e., standing height or less), often affecting hips or wrists. Usually, a lower bone density is associated with higher risk of fractures. However, patients with type 2 diabetes have increased bone fragility despite normal or higher bone density. One reason for this could be the chronically high levels of blood sugar in type 2 diabetes, which alter the properties of proteins in the body. It has been shown that the excess sugar molecules effectively ‘react’ with many different proteins, producing harmful compounds in the process, called Advanced Glycation End-products, or AGEs. AGEs are – in turn –thought to affect the structure of collagen proteins, which help hold our tissues together and decrease bone strength. However, the signalling pathways underlying this process are still unclear. To find out more, Leanza et al. studied a signalling molecule, called sclerostin, which inhibits a signalling pathway that regulates bone formation, known as Wnt signaling. The researchers compared bone samples from both diabetic and non-diabetic patients, who had undergone hip replacement surgery. Analyses of the samples, using a technique called real-time-PCR, revealed that gene expression of sclerostin was increased in samples of type 2 diabetes patients, which led to a downregulation of Wnt signaling related genes. Moreover, the downregulation of Wnt genes was correlated with lower bone strength (which was measured by compressing the bone tissue). Further biochemical analysis of the samples revealed that higher sclerostin activity was also associated with higher levels of AGEs. These results provide a clearer understanding of the biological mechanisms behind compromised bone strength in diabetes. In the future, Leanza et al. hope that this knowledge will help us develop treatments to reduce the risk of bone complications for type 2 diabetes patients.
Type 2 diabetes is a long-term metabolic disease characterised by chronic high blood sugar levels. This in turn has a negative impact on the health of other tissues and organs, including bones. Type 2 diabetes patients have an increased risk of fracturing bones compared to non-diabetics. This is particularly true for fragility fractures, which are fractures caused by falls from a short height (i.e., standing height or less), often affecting hips or wrists. Usually, a lower bone density is associated with higher risk of fractures. However, patients with type 2 diabetes have increased bone fragility despite normal or higher bone density. One reason for this could be the chronically high levels of blood sugar in type 2 diabetes, which alter the properties of proteins in the body. It has been shown that the excess sugar molecules effectively ‘react’ with many different proteins, producing harmful compounds in the process, called Advanced Glycation End-products, or AGEs. AGEs are – in turn –thought to affect the structure of collagen proteins, which help hold our tissues together and decrease bone strength. However, the signalling pathways underlying this process are still unclear. To find out more, Leanza et al. studied a signalling molecule, called sclerostin, which inhibits a signalling pathway that regulates bone formation, known as Wnt signaling. The researchers compared bone samples from both diabetic and non-diabetic patients, who had undergone hip replacement surgery. Analyses of the samples, using a technique called real-time-PCR, revealed that gene expression of sclerostin was increased in samples of type 2 diabetes patients, which led to a downregulation of Wnt signaling related genes. Moreover, the downregulation of Wnt genes was correlated with lower bone strength (which was measured by compressing the bone tissue). Further biochemical analysis of the samples revealed that higher sclerostin activity was also associated with higher levels of AGEs. These results provide a clearer understanding of the biological mechanisms behind compromised bone strength in diabetes. In the future, Leanza et al. hope that this knowledge will help us develop treatments to reduce the risk of bone complications for type 2 diabetes patients.
摘要：
2型糖尿病（T2D）与较高的骨折风险有关，尽管正常或高骨密度。我们报道了骨形成基因（SOST和RUNX2）和糖基化终产物（AGEs）在T2D中受损。我们调查了Wnt信号调节及其与T2D中AGEs积累和骨强度的关系来自15名T2D和21名接受髋关节置换术的非糖尿病绝经后妇女的骨组织。骨组织形态计量学显示，T2D（T2D0.249％[0.156-0.366]）与非糖尿病受试者0.352％[0.269-0.454]相比，矿化量低；p=0.053，以及骨强度降低（T2D21.60MPa[13.46-30.10]与非糖尿病受试者76.24MPa[26.81-132.9]；p=0.002）。我们还显示Wnt激动剂LEF-1(p=0.0136)和WNT10B(p=0.0302)的基因表达在T2D中较低。相反，WNT5A的基因表达（p=0.0232），SOST（p<0.0001），GSK3B(p=0.0456)更高，而T2D中胶原(COL1A1)较低(p=0.0482)。AGEs含量与SOST和WNT5A相关(r=0.9231,p<0.0001;r=0.6751,p=0.0322),但与LEF-1和COL1A1呈负相关(r=-0.7500,p=0.0255;r=-0.9762,p=0.0004)。SOST与血糖控制和病程相关(r=0.4846,p=0.0043;r=0.7107,p=0.00174),而WNT5A和GSK3B仅与血糖控制相关(r=0.5589,p=0.0037;r=0.4901,p=0.0051).最后,杨氏模量与SOST呈负相关(r=-0.5675,p=0.0011),AXIN2（r=-0.5523，p=0.0042），和SFRP5(r=-0.4442，p=0.0437)，与LEF-1(r=0.4116,p=0.0295)和WNT10B(r=0.6697,p=0.0001)呈正相关。这些发现表明Wnt信号和AGEs可能是T2D中骨脆性的主要决定因素。
2型糖尿病是一种以慢性高血糖为特征的长期代谢疾病。这反过来又对其他组织和器官的健康产生负面影响，包括骨头.与非糖尿病患者相比，2型糖尿病患者骨折的风险增加。对于脆性骨折尤其如此，这是从短高坠落引起的骨折(即，站立高度或更低)，经常影响臀部或手腕。通常,较低的骨密度与较高的骨折风险相关。然而,2型糖尿病患者尽管骨密度正常或较高,但骨脆性增加.其中一个原因可能是2型糖尿病患者的长期高血糖，改变体内蛋白质的性质。已经表明，过量的糖分子有效地与许多不同的蛋白质“反应”，在这个过程中产生有害的化合物，称为晚期糖基化终产物，或AGEs。AGEs反过来被认为会影响胶原蛋白的结构，这有助于将我们的组织保持在一起并降低骨骼强度。然而,这一过程背后的信号通路仍不清楚.了解更多,Leanzaetal.研究了一个信号分子，叫做硬化蛋白，抑制调节骨形成的信号通路，被称为Wnt信号。研究人员比较了糖尿病和非糖尿病患者的骨骼样本，接受过髋关节置换手术的人.样品分析，使用一种叫做实时PCR的技术，显示2型糖尿病患者样本中硬化蛋白的基因表达增加，这导致了Wnt信号相关基因的下调。此外，Wnt基因的下调与较低的骨强度（通过压缩骨组织来测量）相关。样品的进一步生化分析显示,较高的硬化蛋白活性也与较高水平的AGEs相关。这些结果提供了对糖尿病中骨强度受损背后的生物学机制的更清晰的理解。在未来,Leanzaetal.希望这些知识将帮助我们开发治疗方法，以降低2型糖尿病患者骨并发症的风险。
2型糖尿病是一种以慢性高血糖为特征的长期代谢疾病。这反过来又对其他组织和器官的健康产生负面影响，包括骨头.与非糖尿病患者相比，2型糖尿病患者骨折的风险增加。对于脆性骨折尤其如此，这是从短高坠落引起的骨折(即，站立高度或更低)，经常影响臀部或手腕。通常,较低的骨密度与较高的骨折风险相关。然而,2型糖尿病患者尽管骨密度正常或较高,但骨脆性增加.其中一个原因可能是2型糖尿病患者的长期高血糖，改变体内蛋白质的性质。已经表明，过量的糖分子有效地与许多不同的蛋白质“反应”，在这个过程中产生有害的化合物，称为晚期糖基化终产物，或AGEs。AGEs反过来被认为会影响胶原蛋白的结构，这有助于将我们的组织保持在一起并降低骨骼强度。然而,这一过程背后的信号通路仍不清楚.了解更多,Leanzaetal.研究了一个信号分子，叫做硬化蛋白，抑制调节骨形成的信号通路，被称为Wnt信号。研究人员比较了糖尿病和非糖尿病患者的骨骼样本，接受过髋关节置换手术的人.样品分析，使用一种叫做实时PCR的技术，显示2型糖尿病患者样本中硬化蛋白的基因表达增加，这导致了Wnt信号相关基因的下调。此外，Wnt基因的下调与较低的骨强度（通过压缩骨组织来测量）相关。样品的进一步生化分析显示,较高的硬化蛋白活性也与较高水平的AGEs相关。这些结果提供了对糖尿病中骨强度受损背后的生物学机制的更清晰的理解。在未来,Leanzaetal.希望这些知识将帮助我们开发治疗方法，以降低2型糖尿病患者骨并发症的风险。
