Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis.

PURPOSE: Several observational studies suggest that estrogens could bias pain perception. To evaluate the influence of estrogenic impregnation on pain expression, a prospective, randomized, controlled, blinded study was conducted in a Sprague-Dawley rat model of surgically induced osteoarthritis (OA). METHODS: Female rats were ovariectomized and pre-emptive 17ß-estradiol (0.025 mg, 90-day release time) or placebo pellets were installed subcutaneously during the OVX procedures. Thirty-five days after, OA was surgically induced on both 17ß-estradiol (OA-E) and placebo (OA-P) groups. Mechanical hypersensitivity was assessed by static weight-bearing (SWB) and paw withdrawal threshold (PWT) tests. Mass spectrometry coupled with high-performance liquid chromatography (HPLC-MS) was performed to quantify the spinal pronociceptive neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), somatostatin (SST), and dynorphin-A (Dyn-A). RESULTS: Compared to control, ovariectomized rats presented higher SP (P = 0.009) and CGRP (P = 0.017) concentrations. OA induction increased the spinal level of SP (+ 33%, P < 0.020) and decreased the release of BK (- 20%, (P < 0.037)). The OA-E rats at functional assessment put more % body weight on the affected hind limb than OA-P rats at D7 (P = 0.027) and D56 (P = 0.033), and showed higher PWT at D56 (P = 0.009), suggesting an analgesic and anti-allodynic effect of 17ß-estradiol. Interestingly, the 17ß-estradiol treatment counteracted the increase of spinal concentration of Dyn-A (P < 0.016) and CGRP (P < 0.018). CONCLUSION: These results clearly indicate that 17ß-estradiol interfers with the development of central sensitization and confirm that gender dimorphism should be considered when looking at pain evaluation.

Pain characterization and response to palliative care in dogs with naturally-occurring appendicular osteosarcoma: An open label clinical trial.

This study aimed to characterize bone cancer pain (quantitative sensory testing (QST), stance asymmetry index, actimetry, scores of pain and quality of life (QoL)) in dogs with appendicular osteosarcoma (OSA), and to evaluate a stepwise palliative analgesic treatment. The pain profile of thirteen client-owned dogs with OSA was compared with seven healthy dogs. Dogs with OSA were then enrolled in a prospective, open-label, clinical trial. Outcome measures included: primary and secondary mechanical thresholds (MT), conditioned pain modulation (CPM), stance asymmetry index, actimetry (most and least active periods), visual analog scales and QoL. After baseline assessments, stepwise treatment comprised orally administered cimicoxib (2 mg/kg q 24h), amitriptyline (1-1.5 mg/kg q 24h) and gabapentin (10 mg/kg q 8h); re-evaluations were performed after 14 (D14), 21 (D21) and 28 (D28) days, respectively. Statistics used mixed linear models (α = 5%; one-sided). Centralized nociceptive sensitivity (primary and secondary MT, and dynamic allodynia) was recorded in OSA dogs. Healthy dogs had responsive CPM, but CPM was deficient in OSA dogs. Construct validity was observed for the QST protocol. Asymmetry index was significantly present in OSA dogs. The CPM improved significantly at D14. When compared with baseline (log mean ± SD: 4.1 ± 0.04), most active actimetry significantly improved at D14 (4.3 ± 0.04), D21 and D28 (4.2 ± 0.04 for both). When compared with baseline, least active actimetry significantly decreased after treatment at all time-points indicating improvement in night-time restlessness. No other significant treatment effect was observed. Except for tactile threshold and actimetry, all outcomes worsened when gabapentin was added to cimicoxib-amitriptyline. Dogs with bone cancer are affected by widespread somatosensory sensitivity characterized by peripheral and central sensitization and have a deficient inhibitory system. This severe pain is mostly refractory to palliative analgesic treatment, and the latter was only detected by specific and sensitive outcomes.

Refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians: detection of naturally occurring osteoarthritis in laboratory cats.

Objectives Feline osteoarthritis causes pain and disability. Detection and measurement is challenging, relying heavily on owner report. This study describes refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians. Methods A video analysis of osteoarthritic (n = 6) and non-osteoarthritic (n = 4) cats facilitated expansion of scale items. Three successive therapeutic trials (using gabapentin, tramadol and oral transmucosal meloxicam spray) in laboratory cats with and without natural osteoarthritis (n = 12-20) permitted construct validation (assessments of disease status sensitivity and therapeutic responsiveness) and further scale refinements based on performance. Results Scale osteoarthritic sensitivity improved from phase I to phase III; phase III scale total score ( P = 0.0001) and 4/5 subcategories - body posture ( P = 0.0006), gait ( P = 0.0031), jumping (0.0824) and global distance examination ( P = 0.0001) - detected osteoarthritic cats. Total score inter-rater (intra-class correlation coefficients [ICC] = 0.64-0.75), intra-rater (ICC = 0.90-0.91) and overall internal consistency (Cronbach's alpha = 0.85) reliability were good to excellent. von Frey anesthesiometer-induced paw withdrawal threshold increased with gabapentin in phase I, in osteoarthritic cats ( P <0.001) but not in non-osteoarthritic cats ( P = 0.075). Night-time activity increased during gabapentin treatment. Objective measures also detected tramadol and/or meloxicam treatment effects in osteoarthritic cats in phases II and III. There was some treatment responsiveness: in phase I, 3/10 subcategory scores improved ( P <0.09) in treated osteoarthritic cats; in phase II, 3/8 subcategories improved; and in phase III, 1/5 subcategories improved ( P <0.096). Conclusions and relevance The revised scale detected naturally occurring osteoarthritis, but not treatment effects, in laboratory cats, suggesting future potential for screening of at-risk cats. Further study is needed to confirm reliability, validity (disease sensitivity and treatment responsiveness) and clinical feasibility, as well as cut-off scores for osteoarthritic vs non-osteoarthritic status, in client-owned cats.

Capsular Biofilm Formation at the Interface of Textured Expanders and Human Acellular Dermal Matrix: A Comparative Scanning Electron Microscopy Study.

BACKGROUND: Despite benefits in reducing capsular contractures, textured implants have been associated with significant pitfalls, such a propensity for biofilm formation. Few studies have investigated whether the use of acellular dermal matrix on textured implants produces similar findings. This study aims to characterize biofilm formation at the capsular-acellular dermal matrix interface with scanning electron microscopy. METHODS: The authors performed a prospective observational pilot study in patients undergoing two-stage expander-to-permanent implant exchange. Patients were inflated with Biocell or Siltex expanders, and specimens from the capsular-pectoralis interface and capsular-acellular dermal matrix interface were obtained and examined under scanning electron microscopy for capsular ingrowth and biofilm formation using the Van Herdeen Biofilm Grading System and the Biofilm Thickness Grading Scale. RESULTS: Nine patients including 14 breasts (28 capsular samples in total) were examined. Thick biofilm formation was observed in all specimens from the capsular-acellular dermal matrix interface with Biocell and 25 percent of capsule-pectoralis interface, whereas no biofilm formation was found in Siltex implants. For Biocell implants, a significant difference in biofilm coverage between the upper and lower poles was observed using the Van Herdeen Biofilm Grading System (p = 0.0028) and the Biofilm Thickness Grading Scale (p = 0.0161). CONCLUSIONS: Biocell implants produce a significant rate of biofilm formation over acellular dermal matrix-covered capsules, which is not present in the muscular region or in Siltex implants. Further randomized controlled trials will further elucidate the clinical impact of using acellular dermal matrices with macrotextured implants. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Translational pain assessment: could natural animal models be the missing link?

Failure of analgesic drugs in clinical development is common. Along with the current "reproducibility crisis" in pain research, this has led some to question the use of animal models. Experimental models tend to comprise genetically homogeneous groups of young, male rodents in restricted and unvarying environments, and pain-producing assays that may not closely mimic the natural condition of interest. In addition, typical experimental outcome measures using thresholds or latencies for withdrawal may not adequately reflect clinical pain phenomena pertinent to human patients. It has been suggested that naturally occurring disease in veterinary patients may provide more valid models for the study of painful disease. Many painful conditions in animals resemble those in people. Like humans, veterinary patients are genetically diverse, often live to old age, and enjoy a complex environment, often the same as their owners. There is increasing interest in the development and validation of outcome measures for detecting pain in veterinary patients; these include objective (eg, locomotor activity monitoring, kinetic evaluation, quantitative sensory testing, and bioimaging) and subjective (eg, pain scales and quality of life scales) measures. Veterinary subject diversity, pathophysiological similarities to humans, and diverse outcome measures could yield better generalizability of findings and improved translation potential, potentially benefiting both humans and animals. The Comparative Oncology Trial Consortium in dogs has pawed the way for translational research, surmounting the challenges inherent in veterinary clinical trials. This review describes numerous conditions similarly applicable to pain research, with potential mutual benefits for human and veterinary clinicians, and their respective patients.

Spinal neuropeptide modulation, functional assessment and cartilage lesions in a monosodium iodoacetate rat model of osteoarthritis.

BACKGROUND AND AIMS: Characterising the temporal evolution of changes observed in pain functional assessment, spinal neuropeptides and cartilage lesions of the joint after chemical osteoarthritis (OA) induction in rats. METHODS AND RESULTS: On day (D) 0, OA was induced by an IA injection of monosodium iodoacetate (MIA). Rats receiving 2mg MIA were temporally assessed at D3, D7, D14 and D21 for the total spinal cord concentration of substance P (SP), calcitonin gene related-peptide (CGRP), bradykinin (BK) and somatostatin (STT), and for severity of cartilage lesions. At D21, the same outcomes were compared with the IA 1mg MIA, IA 2mg MIA associated with punctual IA injection of lidocaine at D7, D14 and D21, sham (sterile saline) and naïve groups. Tactile allodynia was sequentially assessed using a von Frey anaesthesiometer. Non-parametric and mixed models were applied for statistical analysis. Tactile allodynia developed in the 2mg MIA group as soon as D3 and was maintained up to D21. Punctual IA treatment with lidocaine counteracted it at D7 and D14. Compared to naïve, [STT], [BK] and [CGRP] reached a maximum as early as D7, which plateaued up to D21. For [SP], the increase was delayed up to D14 and maintained at D21. No difference in levels of neuropeptides was observed between MIA doses, except for higher [STT] in the 2mg MIA group (P=0.029). Neuropeptides SP and BK were responsive to lidocaine treatment. The increase in severity of cartilage lesions was significant only in the 2mg MIA groups (P=0.01). CONCLUSION: In the MIA OA pain model, neuropeptide modulation appears early, and confirms the central nervous system to be an attractive target for OA pain quantification. The relationship of neuropeptide release with severity of cartilage lesions and functional assessment are promising and need further validation.

Comparison of lidocaine and lidocaine-epinephrine for the paravertebral brachial plexus block in dogs.

OBJECTIVE: To compare the motor and sensory block efficacy and duration of a modified paravertebral brachial plexus block (PBPB) after administration of lidocaine alone (LI) or combined with epinephrine (LE). STUDY DESIGN: Prospective, randomized, blinded, crossover study. ANIMALS: A total of eight healthy female Beagle dogs. METHODS: Under general anesthesia, modified PBPB was performed on the left thoracic limb using neurostimulation and/or ultrasound guidance to administer lidocaine (2 mg kg-1; 0.2 mL kg-1) either alone (treatment LI, n = 10) or with epinephrine (1:100,000; treatment LE, n = 9). Sensory block was evaluated through reaction to a painful mechanical stimulus applied at five sites on the limb. Motor block effect was evaluated according to visual gait assessments and thoracic limb vertical force measurements under dynamic and static conditions. Data were analyzed using repeated-measures generalized estimating equations. All statistical tests were performed two-sided at the α = 0.05 significance threshold. RESULTS: The duration of sensory block did not differ significantly between treatments. Visible gait impairment was more persistent in LE than in LI (118 ± 63 minutes for LI and 163 ± 23 minutes for LE; mean ± standard deviation) (p = 0.027). At nadir value, dynamic peak vertical force was lower in LE than in LI (p = 0.007). For both dynamic and static evaluations, the nadir and the return to baseline force were delayed in LE (return to normal at 180-200 minutes) when compared with LI (130-140 minutes) (p < 0.005). CONCLUSIONS AND CLINICAL RELEVANCE: The addition of epinephrine to lidocaine prolonged the duration and increased the intensity of the regional block, as verified by visual gait assessment and kinetic analysis. No significant difference was noted between treatments regarding sensory blockade. Kinetic analysis could be useful to evaluate regional anesthetic effect in dogs.

Clinical effects of a constant rate infusion of remifentanil, alone or in combination with ketamine, in cats anesthetized with isoflurane.

OBJECTIVE: To evaluate the effects of a constant rate infusion of remifentanil, alone or in combination with ketamine, in healthy cats anesthetized with isoflurane. DESIGN: Randomized, controlled, clinical trial. ANIMALS: 23 cats undergoing elective ovariohysterectomy. PROCEDURES: Cats were premedicated with acepromazine and morphine; anesthesia was induced with propofol and maintained with isoflurane. Cats were given constant rate infusions of remifentanil (20 µg/kg/h [9 µg/lb/h], IV; n = 8), remifentanil and ketamine (0.5 mg/kg [0.23 mg/lb], then 1.8 mg/kg/h [0.82 mg/lb/h], IV; 7), or crystalloid fluids (8). The anesthesiologist was blinded to treatment group, end-tidal isoflurane concentration, and vaporizer setting. Heart rate, systolic arterial blood pressure, respiratory rate, end-tidal partial pressure of CO2, temperature, and end-tidal isoflurane concentration were monitored; recovery scores were assigned. RESULTS: There were no significant differences among treatment groups with respect to age, body weight, surgery time, anesthesia time, time to extubation, recovery score, or cardiorespiratory variables. End-tidal isoflurane concentration was significantly reduced in cats given remifentanil and ketamine (mean ± SD, 0.63 ± 0.4%), compared with concentration in cats given crystalloid fluids (1.22 ± 0.5%) but not compared with concentration in cats given remifentanil alone (1.03 ± 0.4%). Compared with cats given crystalloid fluids, mean isoflurane requirement was reduced by 48.3% in cats given remifentanil-ketamine and 15.6% in cats given remifentanil alone. CONCLUSIONS AND CLINICAL RELEVANCE: At the dosages administered, a constant rate infusion of remifentanil-ketamine resulted in a significant decrease in the isoflurane requirement in healthy cats undergoing ovariohysterectomy. However, significant differences in cardiovascular variables were not observed among treatment groups.

Evaluation of osteoarthritis in cats: novel information from a pilot study.

OBJECTIVE: To describe structural changes associated with osteoarthritis (OA) in cats and to quantify OA-associated disability using functional evaluations. STUDY DESIGN: Cross-sectional pilot study with longitudinal data. ANIMALS: Normal cats (n = 2) and coxofemoral joint OA cats (n = 4) were evaluated by physical examination, radiography, and magnetic resonance imaging (MRI). METHODS: Structural changes related to OA were scored using computed radiographs (CR) and MRI. Functional evaluation consisted of podobarometric gait analyses performed using a pressure-sensitive mattress and motor activity assessments using collar-attached, accelerometer-based activity sensors. RESULTS: Structural scores for the coxofemoral joint OA-related lesions were lower in normal cats than OA cats for MRI (P = .07). Use of MRI allowed for whole-organ assessment of the coxofemoral joint. Pelvic limb peak vertical ground reaction force (PVF) was higher in normal cats than OA cats (P = .10). During the night, motor activity was greater in normal cats than OA cats (P = .04). PVF was positively correlated with mean motor activity (Spearman coefficient [Rho] = 0.83, P = .04) and negatively correlated with age and MRI structural score (Rho = -0.93 and -0.79, P < .01 and .06, respectively). CONCLUSIONS: This study provides the first description of OA-related lesions in cats using MRI. Gait analysis and accelerometry should be considered as objective tools to characterize OA-associated disability, although these assessments were weakly correlated with structural changes.

Measurements of canine aqueous humor inflammatory mediators and the effect of carprofen following anterior chamber paracentesis.

OBJECTIVES: Phase I: To evaluate levels of prostaglandin E(2) (PGE(2) ), nitrites and nitrates (NO(x) ), tumor necrosis factor-alpha (TNF-α) and expression of inducible cyclo-oxygenase (COX-2), nitric oxide synthase (NOS-2), and matrix metalloproteinases (MMP-3 and -9) in canine aqueous humor following repeated anterior chamber paracenteses (ACP). Phase II: to evaluate the effect of carprofen on PGE(2) , NO(x) , and TNF-α in canine aqueous humor following ACP. ANIMALS STUDIED: Four beagles in phase I and 8 beagles in phase II. PROCEDURES: Phase I: ACP was performed at time (T) 0, 4 and 8 h. Phase II: A randomized, placebo-controlled cross-over design with four dogs per group where carprofen was given 4.4 mg/kg/day on day (D) 1, 2 and 3. ACP was performed at T0 and T1.5 on D3. Statistical analysis was performed with repeated measures anova and post hoc Tukey-Kramer multiple-comparison procedure. In phase II, TNF-α level was analyzed with a Wilcoxon signed-rank test. RESULTS: Phase I: PGE(2) significantly increased (P < 0.0001) to plateau at T4. NO(X) was decreased at T4 (P < 0.06), but increased at T8 (P < 0.0001). COX-2 showed detectable expression only at T8. TNF-α, NOS-2, MMP-3 and -9 were undetectable at all time points. Phase II: At T1.5, PGE(2) was significantly elevated in both groups but was lower in the carprofen group (P = 0.037). NO(x) and TNF-α did not statistically increase in either group. CONCLUSIONS: Following ACP, significant increases in PGE(2) levels confirmed inflammation characterized by a rise of COX-2. The NO(x) pathway took longer to induce as compared with PGE(2) . Carprofen decreased PGE(2) levels and could help control intraocular inflammation.

Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model.

INTRODUCTION: The aim of this prospective, randomized, controlled, double-blind study was to evaluate the effects of tiludronate (TLN), a bisphosphonate, on structural, biochemical and molecular changes and function in an experimental dog model of osteoarthritis (OA). METHODS: Baseline values were established the week preceding surgical transection of the right cranial/anterior cruciate ligament, with eight dogs serving as OA placebo controls and eight others receiving four TLN injections (2 mg/kg subcutaneously) at two-week intervals starting the day of surgery for eight weeks. At baseline, Week 4 and Week 8, the functional outcome was evaluated using kinetic gait analysis, telemetered locomotor actimetry and video-automated behaviour capture. Pain impairment was assessed using a composite numerical rating scale (NRS), a visual analog scale, and electrodermal activity (EDA). At necropsy (Week 8), macroscopic and histomorphological analyses of synovium, cartilage and subchondral bone of the femoral condyles and tibial plateaus were assessed. Immunohistochemistry of cartilage (matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS5)) and subchondral bone (cathepsin K) was performed. Synovial fluid was analyzed for inflammatory (PGE(2) and nitrite/nitrate levels) biomarkers. Statistical analyses (mixed and generalized linear models) were performed with an α-threshold of 0.05. RESULTS: A better functional outcome was observed in TLN dogs than OA placebo controls. Hence, TLN dogs had lower gait disability (P = 0.04 at Week 8) and NRS score (P = 0.03, group effect), and demonstrated behaviours of painless condition with the video-capture (P < 0.04). Dogs treated with TLN demonstrated a trend toward improved actimetry and less pain according to EDA. Macroscopically, both groups had similar level of morphometric lesions, TLN-treated dogs having less joint effusion (P = 0.01), reduced synovial fluid levels of PGE(2) (P = 0.02), nitrites/nitrates (P = 0.01), lower synovitis score (P < 0.01) and a greater subchondral bone surface (P < 0.01). Immunohistochemical staining revealed lower levels in TLN-treated dogs of MMP-13 (P = 0.02), ADAMTS5 (P = 0.02) in cartilage and cathepsin K (P = 0.02) in subchondral bone. CONCLUSION: Tiludronate treatment demonstrated a positive effect on gait disability and joint symptoms. This is likely related to the positive influence of the treatment at improving some OA structural changes and reducing the synthesis of catabolic and inflammatory mediators.

Treatment with tiludronic acid helps reduce the development of experimental osteoarthritis lesions in dogs with anterior cruciate ligament transection followed by reconstructive surgery: a 1-year study with quantitative magnetic resonance imaging.

OBJECTIVE: to investigate over a 1-year period in dogs that underwent extracapsular stabilization surgery (ECS) following anterior cruciate ligament (ACL) transection: whether reconstructive surgery could prevent osteoarthritis (OA) progression and whether treatment with the bisphosphonate tiludronic acid (TA) could improve the chronic evolution of OA structural changes. METHODS: ACL transection was performed on dogs on Day 0 and ECS on Day 28. Dogs were randomly divided into 2 groups: 15 received placebo and 16 were treated with TA (2 mg/kg subcutaneous injection) on Days 14, 28, 56, and 84. Magnetic resonance images were acquired on Days -10, 26, 91, 210, and 357, and cartilage volume was quantified. At sacrifice (Day 364), cartilage from femoral condyles and tibial plateaus was macroscopically and histologically evaluated. Expression levels of MMP-1, -3, -13, ADAMTS-4, -5, BMP-2, FGF-2, IGF-1, TGF-ß1, collagen type II, and aggrecan were determined using real-time RT-PCR. RESULTS: the loss of cartilage volume observed after ACL transection stabilized following ECS. Thereafter, a gradual gain occurred, with the cartilage volume loss on the tibial plateaus reduced at Day 91 (p < 0.02) and Day 210 (p < 0.001) in the TA-treated dogs. At sacrifice, TA-treated dogs presented a reduction in the severity of macroscopic (p = 0.03 for plateaus) and histologic (p = 0.07 for plateaus) cartilage lesions, had a better preserved collagen network, and showed decreased MMP-13 (p = 0.04), MMP-1 and MMP-3 levels. CONCLUSION: our findings indicate that in dogs with ACL transection, ECS greatly prevents development of cartilage volume loss. Treatment with TA provided an additional benefit of reducing the development of OA lesions.

Influence of changes in body weight on peak vertical force in osteoarthritic dogs: a possible bias in study outcome.

OBJECTIVE: Force platform gait analysis is a recognized clinical evaluation tool that captures and documents the in vivo pathomechanics of osteoarthritis (OA). In a clinical trial designed to evaluate the impact of 2 specific diets, an increase in body weight (BW) was observed in lame client-owned dogs. Covariance analysis was used to evaluate the interference of BW changes toward the evolution of peak vertical force (PVF) values. These secondary findings are reported in this study. STUDY DESIGN: Prospective study. ANIMALS: Lame dogs (n=26). METHODS: Dogs with radiographic evidence of OA and low PVF values were fed with 2 specific diets for 30 and 60 days. PVF and BW were recorded at baseline, day 30 (D30), and D90. RESULTS: Mean (+/-SD) PVF values (%BW) did not differ significantly over time (D0: 63.9+/-17.2; D30: 65.5+/-17.4; and D90: 66.5+/-20.1). In contrast, BW (kg) was significantly higher at D90 (41.3+/-7.9) when compared with D30 (39.9+/-8.4) and D0 (40.0+/-8.7). Upon covariance analyses, BW changes interfere significantly with PVF values already normalized in %BW (P=.013). Values of PVF adjusted using BW as a covariate were then 63.4+/-17.1 (D0), 65.0+/-17.3 (D30), and 67.6+/-20.5 (D90), whereas D90 was significantly higher than D0. CONCLUSION: These findings highlighted the interference of changes in BW toward locomotor function of OA dogs when using PVF values normalized in %BW. Exacerbation of lameness when a gain in BW occurred was also sustained, raising a possible bias in clinical study outcomes. CLINICAL RELEVANCE: A BW increase in dogs with OA could exacerbate a preexisting lameness and induce a bias in clinical trials.

Osteophytosis, subchondral bone sclerosis, joint effusion and soft tissue thickening in canine experimental stifle osteoarthritis: comparison between 1.5 T magnetic resonance imaging and computed radiography.

OBJECTIVE: To compare use of 1.5 T magnetic resonance imaging (MRI) and computed radiography (CR) for morphologic and temporal evaluation of osteophytosis, subchondral sclerosis, joint effusion, and synovial thickening in experimentally induced canine stifle osteoarthritis (OA). STUDY DESIGN: Prospective study. ANIMALS: Dogs (n=8). METHODS: CR (mediolateral and caudocranial projections) and MRI (dorsal 3D T1-weighted gradient echo, sagittal 3D SPGR and T2-weighted fast spin echo with fat saturation) were performed at baseline (n=8) and at week 4 (n=5), week 8 (n=8), and week 26 (n=5) after cranial cruciate ligament transection. Osteophytosis, subchondral bone sclerosis, and joint effusion were scored on CR and MRI, and synovial thickening on MRI. RESULTS: MRI was more sensitive than CR for detection of osteophytosis and could better discriminate joint effusion from soft tissue thickening, although scores for these variables strongly correlated between modalities (rho=0.94 [osteophytosis] and 0.80 [effusion]; P<.001). Scores for subchondral bone sclerosis also correlated (rho=0.54, P<.004), although this variable may have been over interpreted on CR. Joint effusion and synovial thickening peaked at week 8, before partially regressing at week 26. Conversely, osteophytosis and sclerosis progressed semi-linearly over 26 weeks. CONCLUSION: MRI is more sensitive than radiography in assessing onset and progression of osteophytosis in canine experimental stifle OA and provides enhanced discrimination between joint effusion and synovial thickening. CLINICAL RELEVANCE: MRI is as a more powerful imaging modality that should be increasingly used in animals to assess the joint related effects of disease-modifying OA drugs.

Licofelone reduces progression of structural changes in a canine model of osteoarthritis under curative conditions: effect on protease expression and activity.

OBJECTIVE: We investigated the effectiveness of licofelone, a combined 5-lipoxygenase and cyclooxygenase inhibitor, on structural changes in the anterior cruciate ligament (ACL) experimental dog model of osteoarthritis (OA) under therapeutic conditions. The effect of drug treatment on the expression and activity of metalloproteases in the OA cartilage was also studied. METHODS: The cranial cruciate ligament of the right stifle joint was surgically sectioned in 14 dogs to create OA lesions. Of these dogs, 7 received placebo treatment and served as OA controls, while 7 were treated with licofelone 2.5 mg/kg twice daily for an 8-week period, starting 4 weeks after surgery. At necropsy, macroscopic evaluations were made of the size of osteophytes and the severity of cartilage lesions on femoral condyles and tibial plateaus. Collagenase and other metalloprotease activity levels in cartilage were measured. Levels of gene expression of matrix metalloprotease (MMP-1), MMP-13, cathepsin K, and ADAMTS-5 were quantified by RT-PCR. RESULTS: Licofelone treatment reduced the development of osteophytes and size of cartilage lesions on the femoral condyles and on the tibial plateaus (p < 0.04). Drug treatment also significantly decreased collagenase (p < 0.02) and metalloprotease (p < 0.04) activities, as well as the levels of gene expression of MMP-1 (p < 0.01), MMP-13 (p < 0.05), cathepsin K, and ADAMTS-5 (p = 0.01). CONCLUSION: Under therapeutic conditions licofelone showed the ability to reduce the progression of structural changes in experimental dog OA. This beneficial effect is likely mediated through decrease in the synthesis of a number of catabolic factors, including proteolytic enzymes, involved in cartilage breakdown.