Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Prometheus - Division of Skeletal Tissue Engineering Leuven, KU Leuven, Leuven, Belgium; Biomaterials - BIOMAT, Department of Oral Health Sciences, KU Leuven, Leuven, Belgium.
Biomaterials - BIOMAT, Department of Oral Health Sciences, KU Leuven, Leuven, Belgium.
Bone. 2021 Sep;150:116008. doi: 10.1016/j.bone.2021.116008. Epub 2021 May 14.
The impact of diabetes mellitus on bone fracture healing is clinically relevant as the patients experience delayed fracture healing. Even though efforts have been made to understand the detrimental effects of type 2 diabetes mellitus (T2DM) on the fracture healing process, the exact mechanisms causing the pathophysiological outcomes remain unclear. The aim of this study was to assess alterations in bone fracture healing (tibial fracture surgery, intramedullary pinning) of diet-induced obese (DIO) mice, and to investigate the in vitro properties of osteochondroprogenitors derived from the diabetic micro-environment. High-resolution contrast-enhanced microfocus X-ray computed tomography (CE-CT) enabled a simultaneous 3D assessment of the amount and spatial distribution of the regenerated soft and hard tissues during fracture healing and revealed that osteogenesis as well as chondrogenesis are altered in DIO mice. Compared to age-matched lean controls, DIO mice presented a decreased bone volume fraction and increased callus volume and adiposity at day 14 post-fracture. Of note, bone turnover was found altered in DIO mice relative to controls, evidenced by decreased blood serum osteocalcin and increased serum CTX levels. The in vitro data revealed that not only the osteogenic and adipogenic differentiation of periosteum-derived cells (PDCs) were altered by hyperglycemic (HG) conditions, but also the chondrogenic differentiation. Elevated PPARγ expression in HG conditions confirmed the observed increase in differentiated adipocytes in vitro. Finally, chondrogenesis-related genes COL2 and COL10 were downregulated for PDCs treated with HG medium, confirming that chondrogenic differentiation is compromised in vitro and suggesting that this may affect callus formation and maturation during the fracture healing process in vivo. Altogether, these results provide novel insights into the alterations of long bone fracture repair and suggest a link between HG-induced dysfunctionality of osteochondroprogenitor differentiation and fracture healing impairment under T2DM conditions.
糖尿病对骨折愈合的影响具有临床意义，因为患者会经历骨折愈合延迟。尽管人们努力了解 2 型糖尿病 (T2DM) 对骨折愈合过程的有害影响，但导致病理生理结果的确切机制仍不清楚。本研究旨在评估饮食诱导肥胖 (DIO) 小鼠的骨骨折愈合 (胫骨骨折手术，髓内钉固定) 的变化，并研究源自糖尿病微环境的成骨软骨祖细胞的体外特性。高分辨率对比增强微焦点 X 射线计算机断层扫描 (CE-CT) 能够同时对骨折愈合过程中再生的软、硬组织的量和空间分布进行 3D 评估，结果表明 DIO 小鼠的成骨和软骨生成发生改变。与年龄匹配的瘦对照组相比，DIO 小鼠在骨折后 14 天表现出骨体积分数降低、骨痂体积增加和脂肪含量增加。值得注意的是，与对照组相比，DIO 小鼠的骨转换被发现发生改变，证据是血清骨钙素降低和血清 CTX 水平升高。体外数据表明，不仅高血糖 (HG) 条件改变了骨膜来源细胞 (PDC) 的成骨和脂肪分化，而且还改变了软骨分化。在 HG 条件下 PPARγ 表达升高证实了体外观察到的分化脂肪细胞增加。最后，用 HG 培养基处理的 PDCs 中，软骨生成相关基因 COL2 和 COL10 的表达下调，证实体外软骨分化受损，并表明这可能会影响体内骨折愈合过程中的骨痂形成和成熟。总之，这些结果为长骨骨折修复的改变提供了新的见解，并表明 HG 诱导的成骨软骨祖细胞分化功能障碍与 T2DM 条件下的骨折愈合受损之间存在联系。
