Proteoglycan-4 (PRG4) serum concentration is lower in aged mice, and genetic deficiency impacts survival probability, blood parameters, and bone during aging

Abstract

Proteoglycan 4 (PRG4) is a mucin-like glycoprotein best known as a boundary lubricant of articular cartilage; however, it also has anti-inflammatory, anti-fibrotic, and immunomodulatory properties. Loss-of-function mutations in the PRG4 gene in humans result in Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP), a rare disease in which patients often require joint replacements at young ages. However, it remains unknown how circulating PRG4 levels change with age or how PRG4 deficiency affects aging. Therefore, the first objective of this study was to measure serum PRG4 levels in young and aged wild type (WT) mice. We found that serum PRG4 concentration was lower in aged than young WT mice. Next, we assessed the impact of PRG4 deficiency on survival and determined that Prg4 gene trap (GT, PRG4 deficient) mice had lower survival probability than WT mice. Finally, we examined how PRG4 deficiency impacts blood gases, complete blood counts, and bone in middle-aged Prg4 GT mice. Various blood parameters were altered in Prg4 GT mice versus WT and exhibited sexual dimorphism. PRG4 deficiency diminished trabecular and cortical properties of bone in middle-aged mice sex-dependently, and aging and genotype exhibited an interaction effect consistent with accelerated skeletal aging in males. Overall, this study provides an initial examination into changes in serum PRG4 levels with age in WT mice as well as the effect of PRG4 deficiency in aging. These findings pave the way for future studies to expand on this work mechanistically and assess clinical relevance in CACP and in aging populations.