1. Introduction

Mice and rats, those diminutive yet biologically intricate creatures, serve as invaluable sentinels in the labyrinthine world of human disease exploration. Among the myriad of ailments they illuminate, rheumatoid arthritis (RA) stands as a prominent domain. These unassuming creatures proffer an array of advantages to discerning researchers: their straightforward maintenance, abbreviated reproductive cycles, genetic semblance to Homo sapiens, and genetic tweakability, just to name a few ^[1]. In this intricate narrative of RA, wherein genetic susceptibility, environmental enigmas, and the fervent proclamations of inflammatory cytokines such as TNF-α and interleukins orchestrate the dramatic crescendo ^[2], the quest for efficacious treatments unfolds. The present arsenal, replete with stalwart soldiers like disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs), has indomitably confronted RA's onerous onslaught. Yet, beneath their valorous veneer, lurk the lurking shadows of pernicious side effects that cast long shadows over long-term usage.

But behold, the wisdom of the ages, encapsulated in the treasures of Traditional Chinese Medicines (TCM), beckons as a siren's song amidst these tumultuous waters. Within their ancient pharmacopeias lie promises of respite, as they deftly navigate the labyrinthine corridors of RA with efficacy, minimal side effects, and a diverse array of therapeutic modalities. However, an enigmatic veil shrouds their potential, for the validation of TCM efficacy in the crucible of animal models remains an unfolding narrative, awaiting its denouement  ^[1][2].

The emergence of animal models from the crucible of scientific ingenuity to peer into the secrets of RA's pathogenesis. Through their lens, we may unravel the enigma of genetic susceptibility, demystify the capricious influences of environmental factors, and decode the arcane language of inflammatory cytokines. As we navigate the labyrinthine passages of these models, we endeavor to provide you, the discerning reader, with an illuminating compendium. Armed with knowledge, you may tread confidently, selecting the most fitting model to serve as your guide on your research journey.

2. Streptococcal Cell Wall-Induced Arthritis (SCWIA)

Streptococcal cell wall-induced arthritis (SCWIA) is a model that closely mimics human RA. Bacterial cell wall peptidoglycans possess pro-inflammatory properties relevant to rheumatic diseases. They can trigger acute inflammation by directly activating the complement system. SCW-specific antibody responses and cartilage and bone destruction depend on toll-like receptor (TLR)-4, indicating a shift from innate to adaptive immune involvement during the chronic phase of the disease ^[3][4].

SCWIA clinically, histologically, and radiologically resembles RA in humans. It manifests as symmetrical peripheral joint involvement, differentiating it from other models like AIA. SCWIA and AIA, while similar, exhibit differences in the clinical course, with AIA being monophasic, while SCWIA is biphasic ^[5][6][7].

The development of SCWIA is influenced by various factors, including infection and stress. A pathogen-free environment and widely spaced housing are crucial for successfully inducing SCWIA. Genetic and immunological mechanisms also play a role in determining susceptibility to arthritis in this model. Incidence varies between rat strains, and hormonal factors, sex-linked effects, and host genetic background are important contributors to susceptibility ^[8][9].

3. Collagen-Induced Arthritis (CIA)

Collagen-induced arthritis (CIA) is a widely used model for studying RA. It is induced by immunizing animals with collagen type II (CII), the main component of articular cartilage. After immunization, animals develop autoimmune-mediated polyarthritis that closely resembles human RA in clinical, histological, radiological, and immunological aspects.

In CIA, B cells play a significant role, and B cell-deficient mice do not develop type II CIA. The immune response to CII involves stimulating collagen-specific T and B cells, leading to the production of high titers of antibodies specific to immunogens and autoantigens ^[10]. Various type II collagens from different species can induce CIA in susceptible mouse strains, with differences observed between mouse strains and their sensitivity to these collagens ^[11]. The rat model of CIA offers advantages, with some rat strains, such as Wistar rats, exhibiting a high incidence of severe arthritis ^[12].

4. Collagen Antibody-Induced Arthritis (CAIA)

Collagen antibody-induced arthritis (CAIA) is induced by administering monoclonal antibodies targeting CII. CAIA shares several characteristics with CIA, including macrophage infiltration and inflammatory cell presence in joints. However, it does not involve T and B cell responses, making it distinct from CIA.

CAIA is a rapid model, with acute joint inflammation typically appearing 24-48 hours after immunization  ^[13]. It can be induced in nearly all mouse strains and is independent of MHC alleles, differentiating it from CIA, which is highly susceptible to specific MHC alleles ^[14]. CAIA allows researchers to study common mechanisms involving antibody-mediated diseases and screen candidate drugs for controlling joint inflammation.

5. Proteoglycan-Induced Arthritis (PGIA)

Proteoglycan-induced arthritis (PGIA) is specifically induced in BALB/c mice. PGIA closely resembles human RA in clinical, histological, genetic, and immunological aspects. This model is induced by immunizing mice with deglycosylated human or canine chondroprotein polysaccharide ^[15][16]. Notably, no other mouse strains or laboratory animals, including rats, hamsters, guinea pigs, rabbits, and dogs, are sensitive to PGIA.

PGIA in BALB/c mice exhibits a long development phase, with arthritis appearing approximately 28 days after immunization. The disease onset involves swelling, redness, and edema of synovial and periarticular tissues, followed by massive cell proliferation. The mononuclear cell inflammatory reaction eventually leads to complete degradation of articular cartilage, bone erosion, and severely deformed peripheral joints  ^[17]. The proximal intervertebral discs of the lumbar spine and tail also become inflamed and degenerate.

The development of PGIA is based on cross-reactive immune responses between immune allogeneic and autologous proteoglycans (PGs), involving autoreactive T cells and autoantibodies against murine PG. These autoantibodies enter joints and bind to cartilage PG, forming IgG immune complexes (ICs). The FcγR is associated with the development of PGIA ^[18][19][20].

6. Adjuvant-Induced Arthritis (AIA): Unraveling the Pathways to Autoimmunity

AIA, initially induced by inoculating rats with a Freund-type water-in-oil emulsion, has evolved into a popular model for studying RA and related arthritic conditions. This monophasic, sub-chronic type of arthritis exhibits aggressiveness, often culminating in complete ankylosis and permanent joint deformities ^[1]. Clinically and serologically, AIA mimics many aspects of human RA, including elevated erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) levels ^[1]. Moreover, the histopathological, radiological, and immune changes in AIA closely resemble those seen in human RA, making it a valuable model for screening and testing anti-arthritic drugs ^[2][3].

One distinguishing feature of AIA is the well-defined joint-associated target autoantigen, allowing researchers to investigate how external triggers lead to self-recognition. To induce AIA in rats, a single injection of incomplete or complete Freund adjuvant with Mycobacterium tuberculosis (MTB) is administered into the tail base ^[4]. Notably, different rat strains exhibit varying genetic sensitivities to AIA. Lewis rats are often preferred for AIA studies due to their higher incidence of severe and consistent disease, while Sprague-Dawley (SD) rats are less genetically susceptible but offer a more cost-effective alternative ^[2]. The choice of rat strain and the variability in disease severity make AIA a versatile model for testing new anti-arthritis drugs ^[2].

However, the AIA model comes with its challenges. Even within inbred Lewis rats, the incidence and severity of arthritis can fluctuate significantly, limiting the predictability of the model. This variability necessitates careful consideration of disease intensity when evaluating different drug classes, highlighting the importance of optimizing experimental conditions.

7. Pristane-Induced Arthritis (PIA): A Unique Perspective on Chronic Inflammation

In contrast to AIA, PIA is induced by injecting the synthetic mineral oil pristane intraperitoneally (i.p.) in mice and rats ^[5][6]. PIA is characterized by a severe, chronic inflammatory arthritis, with variations in disease onset and incidence among susceptible strains ^[7]. Dark Agouti rats are highly sensitive to PIA, exhibiting a rapid onset of acute arthritis, leading to recurrent attacks, and eventually, chronic arthritis ^[7]. This model offers a remarkable 100% rate of osteoclast formation, inflammatory cell infiltration, bone erosion, and new bone formation ^[8].

The intriguing aspect of PIA is its induction by a non-infectious, non-antigenic oil, pristane ^[6]. Furthermore, there is a notable delay between exposure to pristane and the development of the disease ^[7]. The exact mechanisms underlying PIA are still under investigation, but it is believed that pristane promotes autoimmune responses through immune activation triggered by antigens found on microorganisms present in the environment ^[9]. This hypothesis is supported by the observation that maintaining mice in a specific pathogen-free (SPF) environment inhibits PIA development, and returning these mice to a normal environment reinstates susceptibility ^[10].

Histologically, PIA exhibits synovial hyperplasia, polymorphonuclear infiltration, periostitis, cartilage erosion, and progressive marginal erosion, closely resembling the pathological features of RA (32). Furthermore, serological markers such as rheumatoid factor (RF) and antibodies against heat shock proteins and type I and II collagen have been detected in PIA, mirroring the immune responses observed in human RA ^[6][10].

6. Conclusion

In conclusion, the discussed animal models are vital tools for advancing our understanding of rheumatoid arthritis (RA) and related autoimmune conditions. Streptococcal cell wall-induced arthritis (SCWIA) closely replicates human RA, shedding light on its pathogenesis and immune involvement. Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) provide distinct advantages for investigating autoimmune mechanisms, with CIA emphasizing B and T cell responses and CAIA offering a rapid, MHC-independent model. Proteoglycan-induced arthritis (PGIA) in BALB/c mice closely mirrors human RA, contributing insights into genetic and immunological factors. Adjuvant-induced arthritis (AIA) is a cornerstone model, but its variability requires careful consideration in drug studies. Pristane-induced arthritis (PIA) presents a unique perspective on chronic inflammation, emphasizing the role of environmental triggers. Collectively, these models enrich our comprehension of RA, aiding research into its pathogenesis, immune responses, and potential therapeutic interventions.