Promotion of Joint Degeneration and Chondrocyte Metabolic Dysfunction by Excessive Growth Hormone in Mice.
Promotion of Joint Degeneration and Chondrocyte Metabolic Dysfunction by Excessive Growth Hormone in Mice.
复制标题
过量生长激素促进小鼠关节退化和软骨细胞代谢功能障碍。
DOI：
10.1002/art.42470
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Kopchick,JohnJ
中科院分区：
文献类型：
--
作者：
Zhu,Shouan;Liu,Huanhuan;Davis,Trent;Willis,CraigRG;Basu,Reetobrata;Witzigreuter,Luke;Bell,Stephen;Szewczyk,Nathaniel;Lotz,MartinK;Hill,Marcheta;Fajardo,RobertoJ;O'Connor,PatrickM;Berryman,DarleneE;Kopchick,JohnJ
肢端肥大症是一种生长激素（GH）过量的激素紊乱，许多肢端肥大症患者报告关节疼痛。本研究的目的是表征牛GH（bGH）或GH受体拮抗剂（GHa）过表达小鼠的关节病理学。我们还研究了GH对软骨细胞代谢的调节作用。MethodsKnee joints从小鼠过度表达bGH或GHa和WT进行组织学和μCT分析OA病理。此外，来自bGH小鼠的软骨用于代谢组学。小鼠原代软骨细胞从WT或bGH小鼠与或不Pegvisomant（PEG）治疗被用于Q-PCR和海马Respirometry analysis. ResultsBGH小鼠在~13个月的男性和女性增加膝关节退行性变，其特征是软骨结构的损失，膨胀的肥大软骨细胞，滑膜炎，和软骨下板变薄。与WT小鼠相比，bGH中的OARSI和Mankin评分显著更高，也证明了关节病理学。代谢组学揭示了bGH小鼠中广泛的代谢途径的变化，包括β-丙氨酸代谢、色氨酸代谢、赖氨酸降解以及抗坏血酸和醛糖二酸代谢。此外，bGH软骨细胞上调脂肪酸氧化（FAO）和Col 10a的表达增加。GHa小鼠的关节显着保护开发年龄相关的关节退行性变与光滑的关节joint surfaces.ConclusionsThese研究发现，过量的GH促进小鼠关节退行性变，而拮抗GH的行动，通过GHa保护小鼠从OA的发展，这是与软骨细胞代谢功能障碍和肥大的变化。
ObjectiveMany patients with acromegaly, a hormonal disorder with excessive growth hormone (GH), report pain in joints. The objective of this study is to characterize the joint pathology of mice with over-expression of either bovine GH (bGH) or a GH receptor antagonist (GHa). We also investigate the effect of GH on regulation of chondrocyte cellular metabolism.MethodsKnee joints from mice over-expressing bGH or GHa and WT were histologically and μCT analyzed for OA pathologies. Additionally, cartilage from bGH mice was used for metabolomics. Mouse primary chondrocytes from WT or bGH mice with or without Pegvisomant (Peg) treatment were used for Q-PCR and Seahorse Respirometry analysis.ResultsBoth male and female bGH mice at ~13 months had increased knee joint degeneration, which is characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher OARSI and Mankin scores in bGH compared with WT mice. Metabolomics revealed changes of a wide range of metabolic pathways in bGH mice including beta-alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes upregulated fatty acid oxidation (FAO) and increased expression of Col10a. Joints of GHa mice are remarkably protected from developing age-associated joint degeneration with smooth articular joint surface.ConclusionsThese studies uncover that an excessive amount of GH promotes joint degeneration in mice, whereas antagonizing GH action through a GHa protects mice from OA development, which is associated with chondrocyte metabolic dysfunction and hypertrophic changes.