Pang Qianqian, Qi Xuan, Chi Yue, Jiajue Ruizhi, Zhang Li, Cui Lijia, Wang Ou, Li Mei, Xing Xiaoping, Jiang Yan, Gong Yiyi, Xia Weibo
Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory for Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China.
Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
J Clin Endocrinol Metab. 2025 Jul 15;110(8):e2591-e2604. doi: 10.1210/clinem/dgae737.
Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder characterized by skeletal and skin abnormalities. Genetic defects in prostaglandin E2 (PGE2) metabolism are known to cause PHO. However, the global impact and clinical significance of eicosanoids and oxylipins beyond PGE2 remain to be elucidated.
This study aimed to investigate oxylipin networks in PHO, including the 2 subtypes, PHOAR1 and PHOAR2, and examine their associations with clinical characteristics.
We conducted a targeted metabolomic study involving 16 patients with PHO and 16 age- and sex-matched healthy controls. Serum samples were collected at the time of diagnosis. Metabolites were quantified using ultra-high-performance liquid chromatography-tandem mass spectrometry.
Laboratory analyses confirmed elevated levels of PGE2 in patients with PHO, consistent with the established pathogenesis. About 60 oxidized lipid metabolites were identified, with 19 differentially expressed in PHO. Besides the COX/PGE2 pathway, the lipoxygenase-mediated pathway was also involved in PHO. The metabolites 5-OxoETE, 15-OxoETE, 8S,15S-DiHETE, PGE2, 11β-PGE2, PGB2, LTB4, and LTE4 were significantly altered. Correlation analyses revealed associations between oxylipin metabolites and clinical features, including bone microarchitecture. Notably, the study highlighted differences in the oxylipin metabolite profiles between patients with PHOAR1 and patients with PHOAR2, suggesting distinct metabolic signatures for each subtype.
Our study indicated a significant perturbation in oxylipin metabolism among patients with PHO, with distinct metabolic signatures observed between PHOAR1 and PHOAR2. The disruption extended beyond the metabolism of PGE2. It encompassed a broader alteration across the polyunsaturated fatty acid metabolism spectrum, including various eicosanoids and oxylipins. Our work provided a comprehensive understanding of the pathogenesis of PHO, and underscored the potential for subtype-specific therapeutic interventions.
原发性肥厚性骨关节病（PHO）是一种罕见的遗传性疾病，其特征为骨骼和皮肤异常。已知前列腺素E2（PGE2）代谢中的基因缺陷会导致PHO。然而，除PGE2之外，类花生酸和氧化脂质的整体影响及临床意义仍有待阐明。
本研究旨在调查PHO中的氧化脂质网络，包括两种亚型PHOAR1和PHOAR2，并研究它们与临床特征的关联。
我们进行了一项靶向代谢组学研究，纳入了16例PHO患者以及16例年龄和性别匹配的健康对照。在诊断时采集血清样本。使用超高效液相色谱-串联质谱法定量代谢物。
实验室分析证实PHO患者中PGE2水平升高，这与既定的发病机制一致。共鉴定出约60种氧化脂质代谢物，其中19种在PHO中差异表达。除COX/PGE2途径外，脂氧合酶介导的途径也参与了PHO。代谢物5-氧代二十碳四烯酸（5-OxoETE）、15-氧代二十碳四烯酸（15-OxoETE）、8S,15S-二氢二十碳四烯酸（8S,15S-DiHETE）、PGE2、11β-PGE2、前列腺素B2（PGB2）、白三烯B4（LTB4）和白三烯E4（LTE4）有显著改变。相关性分析揭示了氧化脂质代谢物与临床特征（包括骨微结构）之间的关联。值得注意的是，该研究突出了PHOAR1患者和PHOAR2患者在氧化脂质代谢物谱方面的差异，表明每种亚型具有独特的代谢特征。
我们的研究表明PHO患者的氧化脂质代谢存在显著紊乱，PHOAR1和PHOAR2之间观察到不同的代谢特征。这种紊乱不仅限于PGE2的代谢，还包括多不饱和脂肪酸代谢谱的更广泛改变，包括各种类花生酸和氧化脂质。我们的工作为PHO的发病机制提供了全面的理解，并强调了亚型特异性治疗干预的潜力。
