Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis (PTOA). Based on lipolytic and immunoregulatory actions of norepinephrine, we hypothesized that intra-articular β-adrenergic receptor (βAR) stimulation would suppress PTOA-associated inflammation in the infrapatellar fat pad (IFP) and synovium. We used the βAR agonist isoproterenol to perturb intra-articular metabolism 3.5 weeks after applying a non-invasive single-load compression injury to knees of 12-week-old male and female mice. We examined the acute effects of intra-articular isoproterenol treatment relative to saline on IFP histology, multiplex gene expression of synovium-IFP tissue, synovial fluid metabolomics, and mechanical allodynia. Injured knees developed PTOA pathology characterized by heterotopic ossification, articular cartilage loss, and IFP atrophy and fibrosis. Isoproterenol suppressed the upregulation of pro-fibrotic genes and downregulated the expression of adipose genes and pro-inflammatory genes (, , , , and ) in injured joints of female (but not male) mice. Analysis of published single-cell RNA-seq data identified elevated catecholamine-associated gene expression in resident-like synovial-IFP macrophages after injury. Injury substantially altered synovial fluid metabolites by increasing amino acids, peptides, sphingolipids, phospholipids, bile acids, and dicarboxylic acids, but these changes were not appreciably altered by isoproterenol. Intra-articular injection of either isoproterenol or saline increased mechanical allodynia in female mice, whereas neither substance affected male mice. Acute βAR activation altered synovial-IFP transcription in a sex and injury-dependent manner, suggesting that women with PTOA may be more sensitive than men to treatments targeting sympathetic neural signaling pathways.

中文翻译：

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创伤后骨关节炎小鼠模型中损伤和β-肾上腺素能激活对代谢和炎症介质的性别特异性影响

代谢过程与先天炎症的消退和组织修复密切相关，这是治疗创伤后骨关节炎 (PTOA) 的两个关键步骤。基于去甲肾上腺素的脂肪分解和免疫调节作用，我们假设关节内 β-肾上腺素能受体 (βAR) 刺激会抑制髌下脂肪垫 (IFP) 和滑膜中 PTOA 相关的炎症。在对 12 周龄雄性和雌性小鼠的膝盖进行非侵入性单负荷压缩损伤 3.5 周后，我们使用 βAR 激动剂异丙肾上腺素来扰乱关节内代谢。我们研究了关节内异丙肾上腺素治疗相对于盐水对 IFP 组织学、滑膜-IFP 组织的多重基因表达、滑液代谢组学和机械异常性疼痛的急性影响。受伤的膝关节出现 PTOA 病理，其特征是异位骨化、关节软骨缺失以及 IFP 萎缩和纤维化。异丙肾上腺素抑制雌性（而非雄性）小鼠受损关节中促纤维化基因的上调，并下调脂肪基因和促炎基因（、、、、和）的表达。对已发表的单细胞 RNA-seq 数据的分析发现，损伤后驻留样滑膜-IFP 巨噬细胞中儿茶酚胺相关基因的表达升高。损伤通过增加氨基酸、肽、鞘脂、磷脂、胆汁酸和二羧酸而显着改变滑液代谢物，但异丙肾上腺素并没有明显改变这些变化。关节内注射异丙肾上腺素或盐水会增加雌性小鼠的机械异常性疼痛，而这两种物质都不影响雄性小鼠。急性βAR激活以性别和损伤依赖性方式改变滑膜-IFP转录，这表明患有PTOA的女性可能比男性对针对交感神经信号通路的治疗更敏感。