Post-traumatic osteoarthritis (PTOA) frequently arises following knee injury, such as anterior cruciate ligament (ACL) rupture. Small animal models are critical for studying PTOA pathology and translating therapeutic interventions. Here our objective was to identify key structural PTOA pathologies and evaluate their associations with aberrant pain and function after a clinically relevant ACL injury in a small animal model. This work leveraged a suite of quantitative cartilage and bone analysis techniques using high-resolution contrast-enhanced microcomputed tomography to investigate the associations between pain-related behaviors and structural osteoarthritis pathogenesis throughout the knee joint in rats. We hypothesized that ACL rupture would increase pain sensitization and limb dysfunction and that this would correlate with the development of clinically relevant osteophytes and cartilage lesions at moderate (4 weeks) and severe disease stages (8 weeks). We showed that ACL rupture induced hyperalgesia and prolonged hindlimb weight-bearing dysfunction; these pain-related behaviors were strongly correlated with changes in the tibiofemoral subchondral bone plate, but not with osteophyte formation. Moreover, we show that patella bone pathology correlates strongly with pain sensitivity and limb function. Joint degeneration initially manifested in the posterior aspect of the medial tibiofemoral compartments, as indicated by full-thickness femoral cartilage lesions and tibial osteophytes at 4 weeks and corresponding tibial cartilage hypertrophy and subchondral sclerosis by 8 weeks. The established outcome parameters and association of structural pathogenesis with pain and dysfunction provide a foundation for studying fundamental PTOA disease etiology and testing therapeutic efficacy in a rodent preclinical model.
In men, cystic fibrosis (CF) leads to infertility in over 95% of cases, due to early and progressive atresia of the vas deferens, resulting in obstructive azoospermia. The advent of highly effective modulator therapy has enabled more men with CF to consider parenthood, raising important questions regarding the impact of these treatments on male fertility. Animal models provide major insights into the mechanism of CF-related reproductive tract abnormalities, yet high interspecies variability complicates model selection. Mouse models display heterogeneous phenotype: knock-in or partial knockout models usually remain fertile, whereas complete knockouts may develop vas deferens atresia with aging. Among currently studied models, CF transmembrane conductance regulator (CFTR)-knockout rats more closely reproduce the human phenotype, showing bilateral absence of the vas deferens and epididymal hypoplasia, although they exhibit more pronounced hypospermatogenesis than observed in men. In larger animal models, including ferrets, pigs, sheep and rabbits, absence of the vas deferens duct and epididymis is frequently observed, often with normal testicular histology; however, most studies in these species have mainly focused on neonatal stages, leaving long-term reproductive outcomes uncharacterized. No single model fully replicates human male reproductive pathology in CF. Combining rodent and large-animal models is probably essential to elucidate the mechanisms of vas deferens absence and to assess the long-term effects of CFTR modulators on male spermatogenesis and reproductive outcomes.
The management of postoperative pain is a critical ethical concern and a challenge in laboratory animal research, particularly for mice. Surgical procedures are routinely conducted in mice, but the use of analgesic drugs is underreported and the assessment of their efficacy is limited. This systematic review assesses the efficacy of analgesic drugs for postoperative pain in mice, addressing the influence of various factors, including sex, surgical invasiveness, pain modalities and analgesic classes. A systematic literature search resulted in 48 eligible studies included in the qualitative analysis and 43 in the quantitative analysis. The overall pooled standardized mean difference (SMD) for analgesic drugs was 0.46 (95% confidence interval 0.31 to 0.60), indicating a positive pain-reducing effect. Subgroup analysis revealed that analgesic treatment was significantly more effective in male (SMD 0.84; 0.60 to 1.08) than in female mice, in mild (SMD 0.57; 0.38 to 0.75) than in severe surgical procedures and in reducing evoked pain (SMD 1.12; 0.83 to 1.41) than in reducing spontaneous pain. In addition, almost all analgesic drug classes tested, including opioids, nonsteroidal anti-inflammatory drugs, acetaminophen and local anesthetics were effective in reducing evoked pain but not spontaneous pain (SMD 0.12; -0.03 to 0.27). However, most studies present limitations that could produce a high risk of bias. Taken together, our results indicate that, although analgesic drugs can reduce postoperative pain in mice, their efficacy is reduced in females, severely invasive surgeries and spontaneous pain. Thus, high-quality studies are still needed to answer ethical concerns and to guarantee full analgesia in laboratory mice submitted to surgical procedures.
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, remains one of the major causes of death from infection worldwide, with over a million associated deaths each year. The study of biomarkers for TB is critical for advancing our understanding and management of the disease. Biomarkers, defined as measurable indicators of biological states or conditions, are invaluable for the diagnosis, prognosis and treatment monitoring of TB. Clinical studies have provided critical knowledge on the matter but are also notoriously constrained by economical, ethical and sampling limitations. The use of animal models provides a simpler, more controllable, cost-effective setting with great potential for translation to humans. They also allow the evaluation of biomarkers within the respiratory compartment, when available, which is of particular interest due to the nature of TB pathogenesis. This Review focuses on the current landscape of TB biomarker discovery in several animal models, from invertebrates to large mammals. Here we summarize the basics of host-pathogen immune interaction, describe the main methodological approaches used and highlight the most substantial findings for each animal model studied. Furthermore, we discuss the advantages, challenges and limitations associated with species-specific differences in animal models. We conclude that integrating the data obtained from animal models and human studies is absolutely required to advance the TB field to accelerate the management of this disease.
