In man, the therapeutic application of quinoline carboxylic acid class of anti-bacterial agents (e.g., cinoxacin; nalidixic, pipemidic and oxolinic acids) has generally been directed toward urinary tract infections.’ Studies of toxicologic profiles of these drugs in experimental animals has uncovered an interesting and unusual species susceptibility to articular cartilage injury. When toxic doses of these drugs are orally administered to juvenile dogs, lesions develop in the articular cartilage of the major diarthrodial joints. The lesion consists of one or more fluid-filled vesicles that form within the zona intermedia of the articular cartilage. Coalescence of large vesicles can occur followed by tearing of the superficial layer of cartilage and eventual effacement. Histology has revealed focal chondromalacia that comprises a sharply delineated region of the zona intermedia and consists of matrical rarefaction, necrosis of chondrocytes, and cartilage fasciculation at the lesion Excessive synovial effusions in severely affected joints, most probably account for the clinical manifestations of swollen joints and lameness. Gait abnormalities disappear even if drug administration is continued: and this observation may indicate that joint fluid resorption commences shortly after vesicle development. We have observed articular cartilage vesicles within three days of daily treatment of oxolinic acid at 500 mg/kg, and by fourteen days chondrocyte clusters were arranged along the edge of the lesion. Chondrocyte clusters have been seen in human osteoarthrosis’ and in surgically injured cartilage of rabbits.’ It is thought that these clusters represent a reparative or regenerative change in cartilage.’ To investigate the fine structural changes in this experimental arthropathy, cartilage was collected at necropsy from three-month-old beagle dogs which had received the following treatments: group 1: one dog was given 500 mg/kg body weight of oxolinic acid for two weeks; group 2: three dogs were treated with 500 mg/kg body weight of oxolinic acid for two weeks followed by a fourweek drug withdrawal; and group 3: four untreated dogs served as controls (one dog killed after two weeks; the remaining three dogs killed after four weeks). In treated animals, all the major synovial joints were affected, as reported previ0us1y.~ For purposes of comparison, articular cartilage was taken only from the right humeral head of each treated and control dog. The lesion occurred on the articulating surface of the humeral head confined to an area adjacent to the lesser tubercle. One-mm cubes were derived from slivers of cartilage collected at the edge of the lesion or from the same anatomic site in the control dogs. Each sliver included the zona superficialis down to the zona profunda of the articular cartilage but excluded the underlying subchondral bone. Tissue specimens were fixed in 2.5% glutaraldehyde, post-fixed in 1 % phosphate buffered osmium tetroxide, dehydrated in a graded ethanol series, and flat embedded in epon to yield five embedded blocks per dog. From these blocks, selection of tissue sections for transmission electron microscopy was based on light microscopic examination of 1 -pm toluidine blue sections. Following 14 days of drug treatment, articular cartilage vesicles were detected in the group 1 dog and were characterized ultrastructurally by an area with loss of proteoglycan particles and reduced numbers and altered configurations of collagen fibrils. Chondrocyte necrosis was evidenced by the presence of shrunken cells with intensely electron dense nuclei (pyknotic) and cytoplasm; profiles of organelles could not be readily identified. An abundance of matrical lipidic debris located at the periphery of the chondrocyte clusters was a further indication of enhanced in situ necrosis.‘ After four weeks of drug withdrawal, each of the dogs in group 2 had cartilage lesions in which vesicles were converted to a narrow cleft within the zona intermedia and clusters of proliferating chondrocytes were located along the edge of the lesion (fig. 1). Chondrocytes within the clusters had welldeveloped rough endoplasmic reticulum and Golgi apparatus. The territorial matrix consisted of proteoglycan particles and fine fibrils. The outer boundary of the cluster was defined by a stratum of proteoglycan particles, but the lipidic debris observed at 14 days was generally absent (fig. 2). The matrix that lined the cleft was formed of electron dense material in which normal matrical structures could not be recognized (fig. 3), and presumably this material represented degradative products of protein catabolism. Similar matncal changes have been observed in disintegrating cartilage of osteoarthrosis in man.’ Solitary chondrocytes in the surrounding matrix had dilatation and mild vesiculation of rough endoplasmic reticulum. When these cells were compared to chondrocytes in age-matched untreated control dogs from group 3, a decreased density of proteoglycan particles and fine fibrils was evident in cartilage cells of treated dogs. The alterations in rough endoplasmic reticulum and territorial matrix in the solitary chondrocytes indicated an early phase of degeneration (fig. 4). When the drug was withdrawn for four weeks after the
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Jun 1, 1987
Yuji Amano + 1
Open Access