The role of substance P on maintaining ligament homeostasis by inhibiting endochondral ossification during osteoarthritis progression

Osteoarthritis (OA) is characterized by the degeneration of various tissues, including ligaments. However, pathological changes such as chondrogenesis and ossification in ligaments during OA are still unclear. Substance P (SP), a neuropeptide, has various functions including bone metabolism. This study aimed to analyze the expression and function of SP in OA ligaments, and the therapeutic potential of SP agonists in OA mice.Expressions of SP, SOX9, and MMP13 were histologically analyzed in the posterior cruciate ligament (PCL) in humans with OA and Senescence-accelerated mouse-prone 8 (SAMP8) mice as a spontaneous OA model. The effect of SP agonists on chondrogenesis was evaluated using human ligament cells. Finally, SP agonists were administered intraperitoneally to destabilized medial meniscus (DMM) mice, and the PCL was histologically evaluated.In PCL of humans and mice, the expression of SP, SOX9, and MMP13 was upregulated as OA progressed, but their expression was downregulated in severe degeneration. SP and SOX9 were co-expressed in chondrocyte-like cells. In ligament cells, SP agonists downregulated SOX9, RUNX2, and COL10A1. On evaluating chondrogenesis in ligament cells, pellet diameter was reduced in those treated with the SP agonists compared to those untreated. Administration of SP agonists ameliorated PCL degeneration in DMM mice. The Osteoarthritis Research Society and ligament scores in mice with SP agonists were significantly lower than those without SP agonists.SP plays an important role in maintaining ligament homeostasis by inhibiting endochondral ossification during OA progression. Targeting SP has therapeutic potential for preventing ligament degeneration.