Dynamic weight-bearing test during jumping: A sensitive outcome measure of chronic osteoarthritis pain in rats

Abstract

Pain due to osteoarthritis (OA) often occurs during locomotion in the vertical direction when joints are subjected to high mechanical load, e.g. during standing up from a chair or using stairs. To investigate joint pain in OA rat models, dynamic weight-bearing or gait analysis is traditionally conducted during horizontal walking on a flat surface. However, in chronic models of OA, which are of particular translational relevance for the disease, differences in the readouts between OA and control rats are often weak and of high variability leading to an insufficient assay window for drug profiling. To measure pain-related symptoms more sensitively, we conducted a dynamic weight-bearing test in the moment of a strong voluntary mechanical load. For that, we permanently housed rats in a four-story rat colony cage (RCC) and determined hind paw forces during voluntary jumping from one level to the next. This outcome measure was named jump incapacitance. After inducing OA by destabilizing the medial meniscus (DMM), we found that during jumps the average ipsilateral over contralateral hind paw forces were significantly reduced compared with healthy controls (jump incapacitance) from early- (day 7) to late-stage disease (day 90). An intra-articular injection of Zilretta (triamcinolone acetonide extended-release injectable suspension) attenuated OA-induced jump incapacitance after 8 days compared with DMM rats receiving vehicle (p = 0.069). In contrast, a CatWalk test for gait disturbance failed to detect any significant alterations in the chronic course of the DMM model. In conclusion, the dynamic weight-bearing test during jumping represents a novel method to characterize joint pain symptoms even in a slowly progressive OA rat model. It is sensitive, observer independent, relates to clinically relevant endpoints and demonstrates backtranslation of a drug that is approved for the treatment of OA knee pain.

A Review of Recent Innovations in Cartilage Regeneration Strategies for the Treatment of Primary Osteoarthritis of the Knee: Intra-articular Injections

“…In 2021, a rodent colony study with Zilretta showed its possible effect in reducing the difficulty of weightbearing load on the joint. 72 While literature has described a lesser risk for adverse events with Zilretta compared with traditional glucocorticoids, the website for Zilretta (www.zilretta.com) lists potential side effects as "joint pain, headache, joint swelling, back pain, sore throat and runny nose, upper…”

“… 40 , 55 , 81 KGN is known to be chondrogenic, as confirmed in multiple ex vivo cultures and animal models of hyaline cartilage where KGN was shown to stimulate proliferation of cartilage stem cell progenitors. 55 , 72 , 79 , 81 In vitro studies of human chondrocyte OA models have demonstrated that KGN administration results in increased collagen 2:1 expression and decreased matrix metalloproteinase (MMP) expression, promoting the innate properties that support the function of articular cartilage. 40 , 72 These studies have also shown increases in gene expression of interleukin-6 (IL-6) and its receptor, revealing an anti-inflammatory mechanism.…”

“… 55 , 72 , 79 , 81 In vitro studies of human chondrocyte OA models have demonstrated that KGN administration results in increased collagen 2:1 expression and decreased matrix metalloproteinase (MMP) expression, promoting the innate properties that support the function of articular cartilage. 40 , 72 These studies have also shown increases in gene expression of interleukin-6 (IL-6) and its receptor, revealing an anti-inflammatory mechanism. 40 This study also observed chondrogenesis in the KGN-treated model with an increased concentration of CD44+/CD105+ HSCs, potentially stimulated via the IL-6/Stat3 pathway.…”

“…In 2021, a rodent colony study with Zilretta showed its possible effect in reducing the difficulty of weightbearing load on the joint. 72 While literature has described a lesser risk for adverse events with Zilretta compared with traditional glucocorticoids, the website for Zilretta ( www.zilretta.com ) lists potential side effects as “joint pain, headache, joint swelling, back pain, sore throat and runny nose, upper respiratory tract infection, and bruising.” 51 With success in these studies, as well as being FDA approved, it is clear that Zilretta is a product that shows promise for knee OA. However, it is still unclear whether Zilretta has any permanent disease-modifying effects.…”

Quercetin and Osteoarthritis: A Mechanistic Review on the Present Documents

“…IL-1β changes chondrocyte homeostatic stability by elevating reactive oxygen species formation, inhibiting anabolic function, and inducing articular cartilage breakdown [12]. Generally, OA patients suffer from periodic arthralgia (joint pain), stiffness, and locomotor restriction symptoms [13, 14]. Among these, the substantial problem for the majority of patients is related to pain [15].…”