Department of Biomedical Sciences, Ohio University, OH, 45701, USA; Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, OH, 45701, USA.
Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Geroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Osteoarthritis Cartilage. 2021 Sep;29(9):1346-1350. doi: 10.1016/j.joca.2021.04.016. Epub 2021 May 10.
'Carbon stress' is a newly found mechanism that links obesity and dysregulated metabolism. It is defined as the cellular accumulation of metabolites during obesity post-translationally modifying metabolic proteins and decreasing their enzymatic activity. The objective of this study was to investigate if 'carbon stress' also occurs in cartilage and contributes to obesity associated OA development.
We histologically evaluated for OA pathology in wild-type (WT) and hyperphagic mice (Pomc-neuron specific enhancer one deficient, Pomc) that were subjected to standard chow (Chow, n = 6 for both genotypes) or high-fat feeding (HFD, n = 7 for both genotypes). Joints were stained and quantified for 'carbon stress' markers, including succinyl-lysine (SCK), malonyl-lysine (MAK), and acetyl-lysine (ACK). Lastly, we used a mouse model with deletion of Sirt5 (n = 7), which is an enzyme that removes SCK and MAK, to test if changing the abundance of 'carbon stress' would affect OA pathogenesis.
Both HFD and Pomc deficiency associated obesity induced cartilage degeneration as well as greater abundance of SCK and MAK in the cartilage. Pomc-HFD mice did not have exacerbated OA pathology as compared to Pomc-Chow mice. ACK was mildly increased in the obese groups comparing to WT-Chow. Sirt5 mice developed early-OA like phenotype at 40 weeks of age as characterized by cartilage fibrillation and more hypertrophic chondrocytes. Cartilage from Sirt5 mice also had increased SCK and MAK, while ACK remained unchanged comparing to WT mice.
Our data suggests that carbon stress also occurs in cartilage tissue during obesity and can potentially contribute to obesity-associated OA.
“碳应激”是一种新发现的机制，它将肥胖症和代谢失调联系起来。它被定义为肥胖症后翻译过程中代谢物在细胞内的积累，从而改变代谢蛋白的结构并降低其酶活性。本研究的目的是探讨“碳应激”是否也发生在软骨中，并导致肥胖相关的 OA 发生。
我们通过组织学评估了野生型（WT）和摄食过度的（Pomc-neuron specific enhancer one deficient，Pomc）小鼠的 OA 病理学，这些小鼠分别接受标准饮食（Chow，两种基因型各 6 只）或高脂饮食（HFD，两种基因型各 7 只）。对关节进行染色并对“碳应激”标志物（包括琥珀酰赖氨酸（SCK）、丙二酰赖氨酸（MAK）和乙酰赖氨酸（ACK））进行定量。最后，我们使用 Sirt5 缺失的小鼠模型（n=7）来测试改变“碳应激”的丰度是否会影响 OA 发病机制，Sirt5 是一种可以去除 SCK 和 MAK 的酶。
HFD 和 Pomc 缺乏引起的肥胖症均导致软骨退化，以及软骨中 SCK 和 MAK 的含量增加。与 Pomc-Chow 相比，Pomc-HFD 小鼠的 OA 病理无明显加重。与 WT-Chow 相比，肥胖组的 ACK 轻度增加。Sirt5 小鼠在 40 周龄时表现出类似于早期 OA 的表型，表现为软骨纤维化和更多的肥大软骨细胞。与 WT 相比，Sirt5 小鼠的软骨中 SCK 和 MAK 增加，而 ACK 保持不变。
我们的数据表明，肥胖症期间软骨组织中也会发生碳应激，并且可能导致肥胖相关的 OA。
