Sustained Exposure of Substance P Causes Tendinopathy

Abstract

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.

Substance P Inhibitor Promotes Tendon Healing in a Collagenase-Induced Rat Model of Tendinopathy

“…The SP-NK1R signaling has been implicated in inducing hypercellularity and collagen production in fibrotic tendinopathy and has been proposed as a therapeutic target for its treatment. 1,12,30 In contrast to previous studies, 1,12,30 this study showed the therapeutic effects of SPI using a rat model of tendinopathy in vivo and has provided evidence to support the proposal of the SP-NK1R pathway as a therapeutic target.…”

“…The harvested specimens were tested to mechanical failure using a universal biomechanical testing machine. 30 The maximum load applied to each specimen was recorded, and the tensile strength was expressed in a unit area (kgf/mm 2 ).…”

“…1 With such a background, the SP-NK1R pathway has been proposed as a therapeutic target. 1,12,30 Specifically, it can be hypothesized that inhibiting NK1R may improve tendinopathies. However, to date, there is a lack of clinical evidence for the practical applications of NK1R antagonists.…”

The Effect of Age and Intrinsic Aerobic Exercise Capacity on the Expression of Inflammation and Remodeling Markers in Rat Achilles Tendons

“…The lack of histological consequences of upregulated expression of substance P and its receptor fits the unaltered expression of tachykinin receptor 1 (Tacr1) and tachykinin 1 gene (Tac1), encoding for substance P and neurokinin A. Nevertheless, substance P was also discussed as a component of tendon healing [ 59 , 60 , 61 , 62 , 63 , 64 ].…”

Substance P, A Promising Therapeutic Target in Musculoskeletal Disorders

“…SP and NK1R increase in the tendons and muscles with overuse [ 56 , 57 , 58 , 59 ], and it has been suggested that the SP-NK1R pathway induces collagen production in overuse tendinopathies [ 56 ]. Thus, the SP-NK1R pathway has been proposed as a therapeutic target for tendinopathy in several recent publications [ 56 , 60 , 61 ]. Andersson et al in particular reported that exogenous SP injections in the paratenon accelerated the development of tendinosis-like changes (hypercellularity and angiogenesis) and resulted in a paratendinous inflammation in the Achilles tendon of a rabbit [ 56 ].…”