Aberrant structure of fibrillar collagen and elevated levels of advanced glycation end products typify delayed fracture healing in the diet-induced obesity mouse model.
Aberrant structure of fibrillar collagen and elevated levels of advanced glycation end products typify delayed fracture healing in the diet-induced obesity mouse model.
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DOI：
10.1016/j.bone.2020.115436
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发表时间：
2020-08
期刊：
影响因子：
4.1
通讯作者：
Elbarbary RA
中科院分区：
文献类型：
--
作者：
Khajuria DK;Soliman M;Elfar JC;Lewis GS;Abraham T;Kamal F;Elbarbary RA
肥胖相关2型糖尿病（T2 D）患者的骨折愈合受损是一个影响全球数百万人的重大未解决的临床问题。然而，人们对根本原因知之甚少。此外，关于肥胖个体中糖尿病前期高血糖症如何影响骨愈合的临床信息有限。在这里，我们使用饮食诱导的肥胖（DIO）小鼠（C57 BL/6 J）模型来研究肥胖相关的糖尿病前期高血糖对骨愈合和纤维胶原组织从一个阶段进入另一个阶段的影响。我们发现DIO小鼠表现出骨矿物质密度、骨体积和骨体积密度降低的愈合缺陷。瘦小鼠和DIO小鼠之间愈合模式的差异发生在愈合过程的早期，如DIO小鼠中纤维软骨愈伤组织的更快吸收所证明的。然而，瘦小鼠和DIO小鼠之间的主要差异发生在软骨内骨化和骨重建的后期阶段。在这些阶段的纤维胶原的微观结构和表达模式的综合分析，使用一组互补的技术，包括组织形态学，免疫荧光染色，和二次谐波发生显微镜，证明在DIO小鼠的显着缺陷。缺陷包括显著稀疏和紊乱的胶原纤维，以及未折叠的胶原三螺旋的病理性积聚。我们还证明，DIO相关的纤维胶原结构的变化是可归因的，至少部分是由于晚期糖基化终产物的积累，这增加了胶原纤维的交联密度。这些主要的变化损害纤维状胶原的功能，最终导致有缺陷的愈伤组织矿化，重塑和强度。我们的数据扩展了对肥胖及其相关高血糖损害骨折愈合机制的理解，并强调了有缺陷的纤维胶原微结构是一种新的重要贡献者。
Impaired fracture healing in patients with obesity-associated type 2 diabetes (T2D) is a significant unmet clinical problem that affects millions of people worldwide. However, the underlying causes are poorly understood. Additionally, limited clinical information is available on how pre-diabetic hyperglycemia in obese individuals impacts bone healing. Here, we use the diet-induced obesity (DIO) mouse (C57BL/6J) model to study the impact of obesity-associated pre-diabetic hyperglycemia on bone healing and fibrillar collagen organization as healing proceeds from one phase to another. We show that DIO mice exhibit defective healing characterized by reduced bone mineral density, bone volume, and bone volume density. Differences in the healing pattern between lean and DIO mice occur early in the healing process as evidenced by faster resorption of the fibrocartilaginous callus in DIO mice. However, the major differences between lean and DIO mice occur during the later phases of endochondral ossification and bone remodelling. Comprehensive analyses of fibrillar collagen microstructure and expression pattern during these phases, using a set of complementary techniques that include histomorphometry, immunofluorescence staining, and second harmonic generation microscopy, demonstrate significant defects in DIO mice. Defects include strikingly sparse and disorganized collagen fibers, as well as pathological accumulation of unfolded collagen triple helices. We also demonstrate that DIO-associated changes in fibrillar collagen structure are attributable, at least in part, to the accumulation of advanced glycation end products, which increase the collagen-fiber crosslink density. These major changes impair fibrillar collagens functions, culminating in defective callus mineralization, remodelling, and strength. Our data extend the understanding of mechanisms by which obesity and its associated hyperglycemia impairs fracture healing and underline defective fibrillar collagen microstructure as a novel and important contributor.
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影响因子：
120.7
作者：
Flegal, Katherine M.;Carroll, Margaret D.;Curtin, Lester R.
通讯作者：
Curtin, Lester R.
影响因子：
3
作者：
Hwang KR;Murrell GA;Millar NL;Bonar F;Lam P;Walton JR
通讯作者：
Walton JR
影响因子：
2.3
作者：
Abraham, Thomas;Fong, Gloria;Scott, Alex
通讯作者：
Scott, Alex
影响因子：
--
作者：
Choi, Yeong-Gon;Lim, Sabina
通讯作者：
Lim, Sabina
影响因子：
4.6
作者：
Hu, Diane P.;Ferro, Federico;Bahney, Chelsea S.
通讯作者：
Bahney, Chelsea S.