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Key Insights | What Are the Animal Models of Rheumatoid Arthritis?

Introduction:

Rheumatoid arthritis (RA) is a common autoimmune disease with a high disability rate, yet its pathogenic mechanisms remain unclear. Establishing appropriate animal models—particularly those that closely resemble the human disease—is of paramount importance for elucidating RA’s pathogenesis and developing effective clinical therapies. This issue’s literature review will introduce you to animal models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that commonly affects the small joints of the hands and feet in a polyarticular, symmetrical pattern and often involves extra-articular organs as well. At present, the etiology and pathogenesis of RA remain incompletely understood, and there are no highly effective targeted therapies available.

 

The most commonly used RA animal models

1. Collagen-induced arthritis (CIA)

(1) Mouse model

The collagen-induced CIA model is one of the most widely used murine models of RA. Using an allogeneic… Type II collagen Immunized animals can induce the organism to produce antibodies against articular cartilage. Type II collagen An autoimmune response, clinically manifested as polyarticular peripheral arthritis.

Modeling method:

Type II collagen was dissolved in acetic acid, stirred at 4°C until fully dissolved, and then stored overnight at 4°C. Inactivated Bacillus Calmette–Guérin (BCG) was suspended in liquid paraffin to prepare complete Freund’s adjuvant (CFA). The two components were mixed in equal volumes and emulsified to yield a type II collagen emulsion. One hundred microliters of this emulsion was injected intradermally into the base of the mouse tail to induce inflammation. On day 21 post‑injection, an additional 100 µL of the type II collagen emulsion was administered intraperitoneally as a boosting injection.

Following the initial immunization injection, mice exhibit a localized inflammatory response that resolves within approximately one week. Twenty-four days after induction of inflammation, the mice develop joint swelling, which progresses from the hind limbs to the forelimbs and eventually to the tail. During the course of the disease, the mice display reduced fur luster, mild hair loss, and weight loss.

 

(2) Rat model

Modeling method: Bovine type II collagen (CII) is emulsified with Freund’s incomplete adjuvant (IFA); on the first day, intradermal immunizations are administered at multiple sites in rats, followed by an intraperitoneal booster injection one week later. A disease model can be established within 3–7 days after the second immunization.

Seven days after sensitization, the ankle joint exhibits mild swelling and erythema; by three weeks, these symptoms worsen, with ulceration of the skin. By five to six weeks, pathological changes are further exacerbated, as both articular cartilage and subchondral bone are eroded and destroyed by pannus tissue.

Susceptible animals include: SD rats, Wistar rats, Lewis rats, DA rats, and others.

Pathology of arthritis

Rat plantar surface

MicroCT of rat arthritis

 

2. Adjuvant-induced arthritis (AA)

The AA model is the most widely used rat RA model, employing Freund’s incomplete adjuvant (IFA) and Complete Freund’s adjuvant (CFA) Two types.

Modeling method: First, a mixed solution prepared by blending liquid paraffin with anhydrous lanolin in a specified ratio is subjected to high-pressure sterilization. The formulation without BCG is designated as IFA, while the one containing BCG is designated as CFA. An inflammatory response is then induced by intradermal injection into rats.

Model features: The modeling method is simple and straightforward; the model typically develops secondary inflammatory symptoms 10–20 days after induction of inflammation, reaching a peak around day 20. The inflammatory manifestations are most pronounced in the ankle joint and may extend to the plantar pad and the entire foot. Joint swelling closely resembles that observed in patients with clinical rheumatoid arthritis, but it is accompanied by immune dysfunction.

Tip: Compared with IFA, CFA includes an additional adjuvant that incorporates mycobacteria, and theoretically, CFA elicits a stronger immune response. Rats are more sensitive than mice, so IFA can also be used; however, CFA is generally preferred.

 

3. Egg-Albumin–Induced Arthritis Model

Modeling method: Most studies use rats. Ovalbumin is dissolved in saline to prepare a 20 g/L solution, which is thoroughly mixed with an equal volume of Freund’s adjuvant. The emulsion is then injected subcutaneously into the animals’ backs, with weekly injections for three consecutive weeks. In the fifth week, 5 mg of dissolved ovalbumin is administered intraarticularly.

This model exhibits a high incidence of disease, with pronounced pathological changes in the egg‑protein–induced arthritis model and prolonged inflammatory persistence.

The egg‑protein–induced arthritis model can also be employed in experimental rabbits, sheep, and other animal species.

 

Other types of RA animal models

I. Induction of Model Mice

1. Diammonium di(stearyl)ammonium (DDA)-induced arthritis (DIA)

This model commonly employs Lewis and DA rats; subcutaneous injection of 2 mg of DDA bromide dissolved in phosphate-buffered saline can induce mild polyarthritis, whereas administration following mixing with IFA can reproduce severe arthritis.

2. Streptococcal Cell-Wall–Induced Arthritis (SCWA)

Modeling method: Intraperitoneal injection of a mixture of peptidoglycan-polysaccharide from Group A streptococcus and other bacteria into rats induces distinct acute arthritis symptoms within 24 hours. Female Lewis (LEW/N) rats are commonly used, and the condition may progress to chronic arthritis in the later stages of induction.

3. Adjuvant-induced arthritis

Modeling method: IFA was combined with inactivated Mtb and administered by subcutaneous injection into the tails of susceptible rats for 14 consecutive days. Arthritic symptoms typically appeared 8 to 12 days after immunization, and over several weeks, the disease progressed rapidly, potentially evolving into destructive arthritis. The most susceptible rat strains are DA or LEW rats. This model closely resembles human rheumatoid arthritis.

4. Avridine-induced arthritis

Modeling method: An experimental rat model of arthritis was established by injecting Avridine into the tails of LEW rats. Female rats exhibited more pronounced and severe symptoms than males.

5. Cartilage Oligomeric Matrix Protein (COMP)-Induced Arthritis

Modeling method: The equal volumes of the COMP solution and complete Freund’s adjuvant were emulsified and then injected intradermally at the base of the tail of susceptible rats.

Susceptible strain: DA and LEW rats. However, a drawback of this model is its poor stability.

6. Pristane-induced arthritis (PIA)

Modeling method: Subcutaneous injection of 300 μL of pristane into the tail of susceptible rats, followed by observation for 2–3 weeks, induces arthritis symptoms; this model can persist for several months.

Susceptible rats: DA and LEW rats.

7. Antigen-induced arthritis (AIA)     

Modeling method: Intradermal injection of a 100-μg mixture of methylated bovine serum albumin (mBSA) and complete Freund’s adjuvant was administered into the skin overlying the femoral head, and additional injections were given into the mouse tail and the knee joint cavity. Starting on day 1, severe arthritic symptoms developed, but these gradually subsided after approximately 3 days.

8. Collagen antibody-induced arthritis (CAIA)

Modeling method: It is induced by a mixture of lipopolysaccharide (LPS) and a monoclonal antibody. The susceptible strain for this model is C57BL/6 mice, which require induction with mouse anti‑type II collagen at a concentration of 10 mg/mL; this can elicit severe, persistent arthritis within a few days.

 

9. Proteoglycan-Induced Arthritis (PGIA)

Modeling method: After emulsifying chondroitin proteoglycan with an adjuvant, mice were intraperitoneally injected at days 0, 21, and 42; erosive arthritis could be induced after 4 weeks.

10. Delayed-type hypersensitivity arthritis ( delayed-type hypersensitivity arthritis,DTHA )

DTHA is an arthritis model that has been developed in recent years, with a 100% incidence rate in C57BL/6 mice.

Modeling method: A mixture of mBSA and CFA, together with anti‑CII antibodies, was injected into the tail of C57BL/6 mice. On day 4, anti‑CII antibodies were administered intravenously, and on day 7, PBS containing mBSA was injected subcutaneously at the base of the right hind paw. Approximately 3–7 days later, the mice developed rapidly progressing severe arthritis in the paws, with inflammation resolving by about day 14.

11. Glucose-6-phosphate isomerase (GPI)

Modeling method: A GPI‑induced RA model was established in DBA/1 mice. Starting on day 35, mild swelling of the toe digits was observed, accompanied by joint erythema, deformity, and impaired mobility.

 

 

12. Lyme disease spirochete–induced arthritis

Modeling method: Bacteria isolated from Borrelia burgdorferi can be used to establish a murine model of rheumatoid arthritis by subcutaneous injection into the dorsum of susceptible C3H, C57BL/6, and BALB/c mice.

13. Streptococcal cell wall–induced arthritis ( streptococcal cell wall-induced arthritis,SCWA )

Modeling method: SCW can induce an acute murine model of arthritis, in which inflammatory cytokines are typically upregulated within a few hours after injection.

Susceptible strains include: BALB/c, DBA/1, and C3H mice. C57BL/6 is a resistant strain.

14. Oil-induced arthritis (OIA)

OIA is a genetically restricted, unique form of arthritis in rats.

Modeling method: A more susceptible DA rat strain was selected to establish an animal model by subcutaneous injection of Freund’s adjuvant (IFA). Typically, arthritis symptoms appear 14 days after injection, with joint swelling that is milder than in other types of arthritis.

Model features: OIA exhibits nearly identical characteristics to CIA, but does not elicit antibodies against CII. Concurrently, it is associated with elevated expression of IL‑2, IFN‑γ, and TNF‑α.

 

II. Transgenic Mice

1. K/BxN mouse (K/BxN TCR-tg) model

Modeling method: In normal mice, injection of K/BxN mouse serum can induce transient clinical signs of arthritis, typically reaching a peak within 10–14 days and then gradually resolving over several weeks. Repeated serum injections can help maintain the model’s durability and stability.

2. TNF-α transgenic mouse model

Modeling method: This mouse model is initially generated by crossing C57BL/6 with CBA and then backcrossing to DBA/1. From 3 to 4 weeks of age, the mice exhibit ankle joint swelling, and by approximately 9 weeks, joint destruction becomes apparent.

3. SKG mouse model

The SKG mouse, derived from a BALB/c genetic background and harboring a mutation at the ZAP‑70 gene locus, is a spontaneous model of arthritis that is highly dependent on the expression of IL‑17 and other cytokines and carries an invisible mutant allele. This model also exhibits extra‑articular manifestations, such as pneumonia and dermatitis.

4. IL-1 receptor antagonist knockout mouse model

This mouse strain typically develops spontaneous arthritis between 5 and 8 weeks after birth. Clinically, it often exhibits inflammatory infiltrates and the formation of pannus.

This animal model must be established using BALB/c mice; it cannot be replicated in other mouse strains.

 

Summary

In recent years, various mouse and rat models of rheumatoid arthritis have become increasingly stable, with the collagen-induced arthritis (CIA) mouse model and the adjuvant-induced arthritis (AA) rat model being the most widely used.

However, to date, no animal model has yet been able to fully recapitulate all the hallmarks of human rheumatoid arthritis. This necessitates a comprehensive evaluation of RA models from both pathological and immunological perspectives, while also leveraging advanced medical imaging techniques to enhance the accuracy and reliability of observations. Such efforts will provide a robust theoretical foundation for future refinements of RA animal models and for the development of novel therapeutics for clinical use.

 

Ailinfei Laboratory offers comprehensive solutions for rheumatoid arthritis animal models.

Different RA disease animal models are established depending on the type of inducing agent, and upon successful model induction, they are evaluated using multiple assessment parameters. Biochemical, pathological, and imaging testing and analysis—offering you a one-stop service experience. Feel free to inquire!

 

 

References:

doi: 10.3969/j.issn.1671-7856.2021.01.023

doi.org/10.1186/s13075-020-02370-1

doi:10.1038/nprot.2007.173

“Methodology for the Replication of Animal Models of Human Diseases,” First Edition, January 2008

 

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