The rheumatic and musculoskeletal diseases (RMD) shape a broad group of conditions in which joint diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA), juvenile idiopathic arthritis (JIA), gout or septic arthritis are largely included [1]. These origin pain and impairment in hundreds of millions of people, just in western countries [2], and drastically harm physical and mental health, with the resulting loss of quality of life and great socioeconomic impact [2], [3], [4], [5], [6], [7].

Animal models have largely contributed to understanding RMD pathogenesis and progression, as well as the development of essential therapies such as the renowned TNF inhibitors [8], [9]. In recent years, a variety of treatments for RMD have emerged, all of which underwent animal testing prior to approval. Notwithstanding the significant breakthroughs, non-responsive patients, side effects or the absence of effectiveness remain a challenge. Hence, there is a pressing need for more innovative solutions and improved efficacy, underscoring the importance of consistent and refined utilization of animal models when screening the physiopathology and pharmacotherapy in RMD.

This review delves into the state-of-the-art for murine models in RMD, from universal to the most accurate options.

The model choice may be influenced not only by the disease in question but also by the objective of the experiment. Therefore, the model selection depends on whether the experimental focus is joint damage, pain, systemic reactions or disease stages.

The murine models in RMD can be spontaneous or induced, and both types include transgenic options (Fig. 1). Spontaneous models represent better the natural and chronic progression of the disease and are useful in the study long-term processes, whilst induced models offer control over disease initiation and are generally more suitable for acute studies and drug testing. Among them, transgenic alternatives focus on the genetic aspects and the role of specific genes [9], [10], [11]. All types provide crucial insights into different aspects of RMD and are complementary between them, so scientists should consider which option better fits their research questions.

Factors such as strain, gender, age, husbandry, diet or welfare conditions [12], [13] can comprise the onset, progression and severity of the disease, and consequently, the design of the study. Behaviour should also be considered since management easiness inevitably hinges on animals. For instance, males or the DBA/1 and C57BL/6 strains tend to be more aggressive [14] although, based on our experience, implementing environmental enrichment, re-caging and careful handling facilitates management over time.For the control of nociceptive pain during research studies, buprenorphine or meloxicam can be administered with low risk of impairing experiment results [15]. Meanwhile neuropathic pain, highly present in chronic arthritis [10], is often controlled by gabapentin [15]. Regardless, it is crucial to establish a humane endpoint when the level of suffering becomes ethically intolerable. According to international guidelines, severe ulcers, persistent (over 72 h) aberrant gait, disabling paw swelling, significant weight loss, spontaneous vocalizations, or any other unjustifiable reason compels humane endpoint [14]. Furthermore, handling and restraint should be done cautiously, assisted by cupped hands, tunnels and containers, while procedures should be executed with care and precision. Adopting these methods greatly minimizes pain and stress.

Also, during pharmacological research, the species-dependant toxicity and metabolism must be considered [16]. For arthritis models, the musculoskeletal system and chronic treatments must be considered during toxicological analyses, while a quick disease progression in rodents compared to humans complicates drug toxicity evaluations [17].