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Recently, neuromediators such as substance P (SP) have been found to be important factors in tendon homeostasis. Some studies have found SP to be the cause of inflammation and tendinopathy, whereas others have determined it to be a critical component of tendon healing. As demonstrated by these conflicting findings, the effects of SP on tendinopathy remain unclear. In this study, we hypothesized that the duration of SP exposure determines its effect on the tendons, with repetitive long-term exposure leading to the development of tendinopathy. First, we verified the changes in gene and protein expression using in vitro tenocytes with 10-day exposure to SP. SP and SP + Run groups were injected with SP in their Achilles tendon every other day for 14 days. Achilles tendons were then harvested for biomechanical testing and histological processing. Notably, tendinopathic changes with decreased tensile strength, as observed in the Positive Control, were observed in the Achilles in the SP group compared to the Negative Control. Subsequent histological analysis, including Alcian blue staining, also revealed alterations in the Achilles tendon, which were generally consistent with the findings of tendinopathy in SP and SP + Run groups. Immunohistochemical analysis revealed increased expression of SP in the SP group, similar to the Positive Control. In general, the SP + Run group showed worse tendinopathic changes. These results suggest that sustained exposure to SP may be involved in the development of tendinopathy. Future research on inhibiting SP is warranted to target SP in the treatment of tendinopathy and may be beneficial to patients with tendinopathy.

It was reported that substance P had beneficial effects in the healing of acute tendon injury. However, the relationship between substance P and degenerative tendinopathy development remains unclear. The purpose of this study was to determine the role of substance P in the pathogenesis of tendinopathy. Healthy and tendinopathy tendon were harvested from human and tenocytes were cultured individually. The expression levels of genes associated with tendinopathy were compared. Next, substance P was exogenously administered to the healthy tenocyte and the effect was evaluated. The results showed that tendinopathy tenocytes had higher levels of COL3A1 , MMP1 , COX2 , SCX , ACTA2 , and substance P gene expression compared to healthy tenocytes. Next, substance P treatment on the healthy tenocyte displayed similar changes to that of the tendinopathy tenocytes. These differences between the two groups were also determined by Western blot. Additionally, cells with substance P had the tendinopathy change morphologically although cellular proliferation was significantly higher compared to that of the control group. In conclusion, substance P enhanced cellular proliferation, but concomitantly increased immature collagen (type 3 collagen). Substance P plays a crucial role in tendinopathy development and could be a future therapeutic target for treatment., Competing Interests: The authors declare no conflict of interest.

Background: The substance P–neurokinin 1 receptor pathway has been proposed as a therapeutic target for tendinopathy. However, there is a lack of evidence regarding its practical applications. Purpose: To investigate the therapeutic effects of substance P inhibitor (SPI) on inflamed tenocytes in vitro and in a collagenase-induced rat model of tendinopathy in vivo. Study Design: Controlled laboratory study. Methods: We analyzed the mRNA levels of inflammatory (cyclooxygenase [COX]-2 and interleukin [IL]-6) and tenogenic (Mohawk and scleraxis [SCX]) markers using reverse transcription quantitative polymerase chain reaction to demonstrate the effects of SPI on lipopolysaccharide-treated (inflamed) tenocytes. A collagenase-induced rat model of tendinopathy was created by injecting 20 µL of collagenase into the Achilles tendon. A behavior test using an incapacitance apparatus was performed to detect changes in postural equilibrium. The tendon specimens were obtained, and their gross findings were examined. The tensile strength was measured, and histopathological evaluation was performed (hematoxylin and eosin, alcian blue, and immunohistochemical staining). Results: The mRNA levels of COX-2, IL-6, Mohawk, and SCX differed significantly between inflamed tenocytes and those treated with SPI. SPI improved the weight burden in a rat model of tendinopathy in a behavioral test. The specimens of the SPI group showed a normal tendon-like appearance. In the biomechanical test, the tensile strength of the SPI group was significantly greater than that of the tendinopathy group. In the histopathological evaluation, the degree of collagen matrix breakdown was mild in the SPI group. In alcian blue staining, only small focal depositions of proteoglycans and glycosaminoglycans were observed in the SPI group. The SPI group showed decreased expression of IL-6 and neurokinin 1 receptor. Conclusion: This study suggests that SPI has therapeutic effects on tendon healing and restoration in a collagenase-induced rat model of tendinopathy. Clinical Relevance: SPI is a promising agent for tendinopathy in humans. [ABSTRACT FROM AUTHOR]

A large number of studies have focused on the role of substance P (SP) and the neurokinin-1 receptor (NK1R) in the pathogenesis of a variety of medical conditions. This review provides an overview of the role of the SP-NK1R pathway in the pathogenesis of musculoskeletal disorders and the evidence for its role as a therapeutic target for these disorders, which are major public health problems in most countries. To summarize, the brief involvement of SP may affect tendon healing in an acute injury setting. SP combined with an adequate conjugate can be a regenerative therapeutic option in osteoarthritis. The NK1R antagonist is a promising agent for tendinopathy, rheumatoid arthritis, and osteoarthritis. Research on the SP-NK1R pathway will be helpful for developing novel drugs for osteoporosis. [ABSTRACT FROM AUTHOR]