JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
April 2022
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 4mm 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 2 x 0.5mm cartilaginous erosion characterized by a loss of the superficial layer and up to 50% of the transitional zone.  This erosion is covered by an approximately 100um thick band of fibrous connective tissue that contains several small caliber blood vessels, forms few projections up to 600um 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 are a group of broad-spectrum antibiotics including enrofloxacin, difloxacin, and ciprofloxacin that act by inhibiting bacterial DNA-gyrase
• High concentrations of fluoroquinolones are chondrotoxic to the articular cartilage of weight-bearing joints
• Articular cartilage is composed of large sulfated proteoglycan aggregates embedded in fibrillar networks of type-II collagen
• Other toxic effects of quinolones are tendonitis and tendon rupture, gastrointestinal upset (vomiting & diarrhea), and neurotoxicosis (convulsions)
• Chondrotoxicity is dependent on compound administered, species of animal, age of animal, and dosage
• Species affected are: Canine, humans, mice, rats, guinea pigs, rabbits, foals, non-human primates; the juvenile dog is the most susceptible 
• Chondrocytes in juvenile dogs are physiologically active

 

PATHOGENESIS:

• Unknown, several proposed mechanisms:
  • Quinolones chelate divalent cations, including magnesium, to form stable complexes resulting in impaired function of integrin receptors on the chondrocytes
    • Chondrocytes require cell-to-matrix interaction, which is primarily mediated by integrins
    • Integrins regulate cell adhesion, proliferation, differentiation, and proteoglycan synthesis
• Quinolones may inhibit synthesis of proteoglycans, DNA, and collagen (types II and IX), and cause chondrocyte mitochondrial dysfunction
• Quinolones have an inhibitory effect on topoisomerase II which may depress DNA synthesis
  • Topoisomerases catalyze and guide the unknotting of DNA; type II topoisomerase cuts both strands, and passes an unbroken double strand through it then reanneals the cut strand
• In a five dog study, ofloxacin inhibited proteoglycan production but did not inhibit DNA/protein synthesis (Yabe, Vet Pathol. 2004)

 

TYPICAL CLINICAL FINDINGS:

• Lameness

 

TYPICAL GROSS FINDINGS: 

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

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Chondrocyte degeneration and necrosis in the intermediate zone of articular cartilage with formation of 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: 

• Glycogen clumping, swollen mitochondria, dilated rough endoplasmic reticulum (initial hallmark), cytoplasmic vacuolation
• Chondrocyte degeneration and necrosis
• Electron lucent pericellular matrix
• Depletion of electron-dense proteoglycan granules

 

DIFFERENTIAL DIAGNOSIS:

• Magnesium deficiency: Articular cartilage lesions are identical
• 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:

• Quinolones produce cartilage defects in young animals of many species including rats, guinea pigs, rabbits, poultry, dogs, horses, humans, and non-human primates
• Cats – fluoroquinolones cause photoreceptor degeneration; susceptibility has genetic basis
  • Specific amino acid changes in ABCG2 at the blood-retinal barrier allow accumulation of drug in retina à fluoroquinolones are photoreactive à light exposure leads to formation of reactive oxygen species à damages lipid membranes in retina à photoreceptor degeneration

 

REFERENCES:

1. Beluche LA, Bertone AL, Anderson DE, Kohn CW, Weisbrode SE. In vitro dose-dependent effects of enrofloxacin on equine articular cartilage. Am J Vet Res. 1999;60:577-582.
2. Burkhardt JE, Hill MA, Turek JJ, Carlton WW. Ultrastructural changes in articular cartilages of immature beagle dogs dosed with difloxacin, a fluoroquinolone. Vet Pathol. 1992;29:230-238.
3. Davenport CLM, Boston RC, Richardson DW. Effects of enrofloxacin and magnesium deficiency on matrix metabolism in equine articular cartilage. Am J Vet Res 2001;62:160-166.
4. Egerbacher M, Wolfesberger B, Gabler C. In vitro evidence for effects of magnesium supplementation in quinolone-treated horse and dog chondrocytes. Vet Pathol. 2001;38:143-148.
5. 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; 2018:775-776,788-789.
6. Labelle P. The eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. St. Louis, MO: Elsevier. 2017:1318.
7. 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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