Excessive downhill training leads to early onset of knee osteoarthritis.

OBJECTIVE: Increased levels of pro-inflammatory cytokines are associated with the release of degradative enzymes leading to osteoarthritis (OA) development. Although physical exercise (PE) is generally recognized as beneficial for OA symptoms, excessive training workload and eccentric muscular exercise have increased OA risk. Here, we investigated the effects of excessive exercise workload and exercise type on systemic inflammation and knee joint OA. METHODS: Mice were divided into five groups: sedentary (SED), uphill training (TRU), downhill training (TRD), excessive uphill training (ETU), and excessive downhill training (ETD) for an 8-week training intervention protocol. RESULTS: ETD group had increased pro-inflammatory cytokines in serum, vastus lateralis (VL), and vastus medialis (VM) muscles, while ETU group mice had increased cytokine levels in the VL and VM. Total knee joint OARSI score were more significant in ETD group compared to SED and TRU groups. They were also more meaningful for the medial tibial plateau of ETD group compared to SED group. MMP-3 and cleaved Caspase-3 were higher in the ETD group than the SED and TRU group, while Adamts-5 was higher in the ETD group than the SED group. TRU group had increased PRG-4 levels compared to ETU and ETD group. ETD group had decreased total bone volume, trabecular bone volume, and cortical thickness compared to SED group. CONCLUSION: Excessive downhill training induced a chronic pro-inflammatory state in mice and was associated with early signs of cartilage and bone degeneration that are clinical indicators of knee OA.

High-fat/high-sucrose diet-induced obesity results in joint-specific development of osteoarthritis-like degeneration in a rat model.

OBJECTIVES: Metabolic syndrome and low-grade systemic inflammation are associated with knee osteoarthritis (OA), but the relationships between these factors and OA in other synovial joints are unclear. The aim of this study was to determine if a high-fat/high-sucrose (HFS) diet results in OA-like joint damage in the shoulders, knees, and hips of rats after induction of obesity, and to identify potential joint-specific risks for OA-like changes. METHODS: A total of 16 male Sprague-Dawley rats were allocated to either the diet-induced obesity group (DIO, 40% fat, 45% sucrose, n = 9) or a chow control diet (n = 7) for 12 weeks. At sacrifice, histological assessments of the shoulder, hip, and knee joints were performed. Serum inflammatory mediators and body composition were also evaluated. The total Mankin score for each animal was assessed by adding together the individual Modified Mankin scores across all three joints. Linear regression modelling was conducted to evaluate predictive relationships between serum mediators and total joint damage. RESULTS: The HFS diet, in the absence of trauma, resulted in increased joint damage in the shoulder and knee joints of rats. Hip joint damage, however, was not significantly affected by DIO, consistent with findings in human studies. The total Mankin score was increased in DIO animals compared with the chow group, and was associated with percentage of body fat. Positive significant predictive relationships for total Mankin score were found between body fat and two serum mediators (interleukin 1 alpha (IL-1α) and vascular endothelial growth factor (VEGF)). CONCLUSION: Systemic inflammatory alterations from DIO in this model system may result in a higher risk for development of knee, shoulder, and multi-joint damage with a HFS diet.Cite this article: K. H. Collins, D. A. Hart, R. A. Seerattan, R. A. Reimer, W. Herzog. High-fat/high-sucrose diet-induced obesity results in joint-specific development of osteoarthritis-like degeneration in a rat model. Bone Joint Res 2018;7:274-281. DOI: 10.1302/2046-3758.74.BJR-2017-0201.R2.

Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model.

UNLABELLED: Osteoarthritis (OA) may result from intrinsic inflammation related to metabolic disturbance. Obesity-associated inflammation is triggered by lipopolysaccharide (LPS) derived from the gut microbiota. However, the relationship between gut microbiota, LPS, inflammation, and OA remain unclear. OBJECTIVE: To evaluate the associations between gut microbiota, systemic LPS levels, serum and local inflammatory profiles, and joint damage in a high fat/high sucrose diet induced obese rat model. METHODS: 32 rats were randomized to a high fat/high sucrose diet (diet-induced obese (DIO), 40% fat, 45% sucrose, n = 21) or chow diet group (12% fat, 3.7% sucrose n = 11) for 28 weeks. After a 12-week obesity induction period, DIO animals were stratified into Obesity Prone (DIO-P, top 33% by change in body mass, n = 7), and Obesity Resistant groups (DIO-R, bottom 33%, n = 7). At sacrifice, joints were scored using a Modified Mankin Criteria. Blood and synovial fluid analytes, serum LPS, and fecal gut microbiota were analyzed. RESULTS: DIO animals had greater Modified Mankin scores than chow animals (P = 0.002). There was a significant relationship (r = 0.604, p = 0.001) between body fat, but not body mass, and Modified Mankin score. Eighteen synovial fluid and four serum analytes were increased in DIO animals. DIO serum LPS levels were increased compared to chow (P = 0.031). Together, Lactobacillus species (spp.) and Methanobrevibacter spp. abundance had a strong predictive relationship with Modified Mankin Score (r(2) = 0.5, P < 0.001). CONCLUSIONS: Increased OA in DIO animals is associated with greater body fat, not body mass. The link between gut microbiota and adiposity-derived inflammation and metabolic OA warrants further investigation.

Using diet-induced obesity to understand a metabolic subtype of osteoarthritis in rats.

UNLABELLED: Osteoarthritis (OA) in obese individuals is often attributed to joint loading. However, a subtype of OA, Metabolic OA, may be due to obesity-related intrinsic factors but remains to be evaluated experimentally against a known OA progression model. OBJECTIVE: To evaluate if obesity contributes to OA onset using a high fat/high sucrose diet-induced obesity (DIO) model with anterior cruciate ligament-transected rats (ACL-X). METHODS: Sprague Dawley rats (n = 33) consumed high fat/high sucrose or chow diets for 12 weeks, were randomized to one of three groups: a unilateral ACL-X group, sham surgery group, or naïve non-surgical group. These animals were followed for an additional 16 weeks. At sacrifice, body composition, knee joint Modified Mankin scores, and 27 serum and synovial fluid cytokines and adipokines were measured. RESULTS: Experimental limbs of obese ACL-X, obese Sham, and lean ACL-X animals had similar Modified Mankin scores that were greater than those obtained from lean Sham and naïve animals. Obese contralateral limbs had similar OA damage as ACL-X and Sham limbs of obese and ACL-X limbs of lean animals. Obese contralateral limb Modified Mankin scores had a strong correlation (r = 0.75, P < 0.001) with body fat percentage. Serum leptin and synovial fluid IP10/CXCL10 best described Modified Mankin scores in contralateral limbs of obese animals. CONCLUSIONS: Mechanical factors produced OA damage in experimental limbs, as expected. Interestingly, OA damage in obese contralateral limbs was similar to mechanically perturbed limbs, suggesting that obesity may induce OA in a non-mechanical manner.