Sex-specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis

Abstract

Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis (PTOA). Here we used the {beta}-adrenergic receptor ({beta}AR) agonist isoproterenol as a tool 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 treatment with isoproterenol relative to saline on pain behavior, histology, multiplex gene expression, and synovial fluid metabolomics. Injured knees developed PTOA pathology characterized by heterotopic ossification, loss of tibial and femoral articular cartilage, and infrapatellar fat pad (IFP) atrophy and fibrosis. Isoproterenol modestly increased IFP atrophy and fibrosis, and it also caused sexually dimorphic and injury-dependent effects on IFP and synovium gene expression. In injured joints of female mice, isoproterenol suppressed the upregulation of pro-fibrotic genes and downregulated the expression of adipose tissue genes and pro-inflammatory genes (Adam17, Cd14, Icam1, Csf1r, and Casp1). 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. Mechanical allodynia was also not altered by isoproterenol, although isoproterenol downregulated the expression of nociception-associated genes, Ngf and Tacr1, in injured IFP-synovium of female mice. Overall, these results suggest that {beta}AR activation functions in a sexually dimorphic manner in PTOA joints. The findings support further exploration of therapeutic strategies that target neuro-metabolic signaling pathways for treating PTOA, particularly in women.