JPC SYSTEMIC PATHOLOGY

MUSCULOSKELETAL SYSTEM

April 2025

M-T05

 

Signalment (JPC # 2329125): 14-week-old male beagle

HISTORY: This dog was part of a toxicologic study.

HISTOPATHOLOGIC DESCRIPTION: Femur (per contributor), articular cartilage: Focally affecting the deep aspect of the transitional zone of the articular cartilage is a 4 mm long, linear fissure that elevates the overlying cartilage, resulting in an uneven and undulant articular surface. Within the fissure, there are few free chondrocytes, scant necrotic debris, and several irregular clusters and strands of eosinophilic fibrillar material (unmasked collagen fibers) that line the margin of the pseudocystic space and project perpendicularly into the lumen (fibrillation). Immediately along the periphery of the fissure, chondrocytes are shrunken and angular with hypereosinophilic cytoplasm and pyknotic to karyolytic nuclei (necrosis) and are embedded within cartilaginous matrix with increased pallor, expanded by clear space and eosinophilic proteinaceous fluid (edema). Peripheral to the necrotic chondrocytes, there are multifocal clusters composed of 2-4 viable chondrocytes within individual lacunae (chondrones). This fissure is adjacent to a 2x0.5 mm cartilaginous erosion characterized by a loss of the superficial layer and up to 50% of the transitional zone. This erosion is partially covered by an approximately 100 um thick band of fibrous connective tissue that contains several small caliber blood vessels, forms few projections up to 600 µm in length extending into the articular space, and is partially covered along the articular luminal surface by attenuated synoviocytes (pannus).

MORPHOLOGIC DIAGNOSIS: Femur (per contributor), articular cartilage, intermediate (transitional) zone: Degeneration and necrosis, focally extensive, moderate, with cleft formation, fibrillation, erosion, and pannus, beagle, canine.

ETIOLOGIC DIAGNOSIS: Quinolone-induced arthropathy

CAUSE: Quinolone compounds

GENERAL DISCUSSION:

• Quinolones/Fluoroquinolones (e.g., enrofloxacin, difloxacin, and ciprofloxacin) are a group of broad-spectrum antibiotics that are occasionally associated with arthropathy or tendinopathy in young animals (in which articular cartilage is still growing) of multiple species, including canine, humans, mice, rats, guinea pigs, rabbits, foals, non-human primates; the juvenile dog is the most susceptible
  • High concentrations of fluoroquinolones are chondrotoxic to the articular cartilage of weight-bearing joints
  • Quinolones have also been associated with premature closure of the growth plate
• Other toxic effects of quinolones are tendonitis and tendon rupture, gastrointestinal dysbiosis, and retinopathy

PATHOGENESIS:

• Quinolones inhibit DNA synthesis via inhibiting bacterial DNA-gyrase and topoisomerase II
• Chondrotoxicity suspected via decreased chondrocyte synthesis of extracellular matrix components (e.g., proteoglycan) and chondrocyte mitochondrial dysfunction (rather than decreased chondrocyte DNA or protein synthesis)
• Articular cartilage is composed of large, sulfated proteoglycan aggregates embedded in fibrillar networks of type-II collagen
  • Quinolones also chelate divalent cations (including magnesium) -> Form stable complexes -> Impaired function of integrin receptors on chondrocytes (chondrocytes cell-to-matrix interaction is primarily mediated by integrins)

TYPICAL CLINICAL FINDINGS:

• Lameness

TYPICAL GROSS FINDINGS:

• Raised, fluid-filled vesicles (blister) on articular surface
• Fissure formation, erosion, cartilage flaps

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Chondrocyte degeneration and necrosis in the intermediate zone of articular cartilage, leading to fissures or cavities -> Vesicle formation
• Decreased extracellular matrix (decreased staining intensity for proteoglycan) and clumping of collagen fibrils
  • Decreased safranin-O staining intensity suggesting proteoglycan depletion

ULTRASTRUCTURAL FINDINGS:

• Chondrocyte: Degeneration (dilated rough endoplasmic reticulum cisterna, glycogen clumping, swollen mitochondria, cytoplasmic vacuolation) progressing to necrosis (nuclear pyknosis)
• Pericellular matrix: Increased lucency with depletion of electron-dense proteoglycan granules

DIFFERENTIAL DIAGNOSIS:

• Magnesium deficiency: Identical articular cartilage lesions
• Osteochondrosis dissecans (OCD) (M-M21): Cartilage lesions are similar, but OCD will have necrosis of cartilage canals and osteosclerosis of underlying subchondral bone +/- infraction, inflammation, osteonecrosis

COMPARATIVE PATHOLOGY:

• Rabbits: Fluoroquinolone arthropathy reported in juvenile New Zealand White rabbits, most commonly associated with articular cartilage of large weight-bearing joints
• Cats: Fluoroquinolones cause photoreceptor degeneration with often permanent blindness; susceptibility has genetic basis
• Specific amino acid changes in ABCG2 at the blood-retinal barrier allow accumulation of drug in retina -> Fluoroquinolones are photoreactive -> Light exposure leads to formation of reactive oxygen species -> Damages lipid membranes in retina -> Photoreceptor degeneration (swelling, vacuolation)

Other antibiotics

• Drug-induced polyarthritis: A type of non-erosive polyarthritis that occurs most commonly following sulfonamide antibiotic administration (especially in Doberman Pinschers); also been associated with phenobarbital, erythropoietin, penicillin, lincomycin, erythromycin, and cephalosporins; signs typically resolve within 5 days of discontinuing drug;
• Non-erosive polyarthritis is a type of immune-mediated polyarthritis (IMPA) caused by circulating antigen-antibody complexes deposited in multiple joints, leading to lymphoplasmacytic synovitis and neutrophils within the synovial fluid and no cartilage erosion; synovial fluid cytology is characterized by a mild to moderate increase in cellularity, mostly nondegenerate neutrophils
• Lab animal (gerbil, guinea pig, rabbit):
• “Antibiotic toxicity”: A term used for enteric dysbiosis secondary to antibiotic therapy (e.g., beta-lactam such as penicillin or ampicillin; clindamycin, erythromycin, or bacitracin) leading to a loss of normal gram-positive organisms (e.g., streptococci and lactobacilli) that predominate in lab animal small/large intestines; associated with Clostridioides difficile, Clostridium perfringens enterotoxemia, Clostridium piliforme (Tyzzer's disease), E. coli, or Clostridium spiroforme (in rabbits) enteritis or typhlocolitis
• Streptomycin causes blocks neuromuscular release of acetylcholine (especially in gerbils) -> depression, ascending paralysis, death

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. In: Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016:180, 201, 208, 224, 316.
2. Gunson D, Gropp KE, Varela A. In: Wallig MA, Haschek WM, Rousseaux CG, et al, eds. Fundamentals of Toxicologic Pathology. San Diego, CA: Academic Press; 2018:775-776,781-782,789-790.
3. Wilcock BP, Njaa BL. Special Senses. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:472.
4. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1433.
5. Yabe K, Satoh H, Ishii Y, et. al. Early pathophysiologic features of arthropathy in juvenile dogs induced by ofloxacin, a quinolone antimicrobial agent. Vet Pathol. 2004;41:673-681.

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