Objective. To evaluate the sequence of changes in articular cartilage, trabecular bone, and subchondral plate in dogs with osteoarthritis (OA), 3 months, 18 months, and 54 months after anterior cruciate ligament transection (ACLT).Methods. Specimens of the medial tibial plateau Submitted for publication May 5 , 1992; accepted in revised form February 9, 1993. were analyzed with microscopic computed tomography (micro-CT) at a resolution of 60 pm, and biochemical and morphologic changes in the femoral articular cartilage were assessed.Results. At 3 months and 18 months after ACLT, the articular cartilage in the unstable knee showed histologic changes typical of early OA and increased water content and uronic acid concentration; by 54 months, full-thickness ulceration had developed. Micro-CT analysis showed a loss of trabecular bone in the unstable knee, compared with the contralateral knee, at all time points. Al. both 18 and 54 months, the differences in trabecular thickness and surface-tovolume ratio were greater than at 3 months. Although the mean subchondral plale thickness, especially in the medial aspect of the medial tibial plateau, was greater in the OA knee than in the contralateral knee 18 months and 54 months after ACLI', these differences were not statistically significant; however, the difference was significantly greater at 54 months than at 3 months.Conclusion. Thickening of the subchondral bone is not required for the development of cartilage changes of OA in this model. The bony changes that develop after ACLT, however, could result in abnormal transmission of stress to the overlying cartilage and thereby contribute to the progression of cartilage degeneration.In the pathogenesis of osteoarthritis (OA), interactions among all the major joint tissues, including the articular cartilage, synovium, and subchondral bone, have been implicated (1). While a large body of work has focused on the alterations in the articular cartilage in OA in humans and experimental animal

Objective. In vitro studies have indicated that levels of neutral metalloproteinases in osteoarthritic (OA) cartilage are elevated and that doxycycline (doxy) inhibits collagenolytic and gelatinolytic activity in extracts of OA cartilage. The purpose of the present study was to test the effect of oral doxy administration on the severity of cartilage degeneration in OA.Methods. OA was induced in 12 adult mongrel dogs by transection of the anterior cruciate ligament (ACL) 2 weeks after dorsal root ganglionectomy. Six dogs received doxy orally from the day after ACL transection until they were killed 8 weeks later; the other 6 served as untreated OA controls.Results. The unstable knee of each untreated dog exhibited extensive full-thickness cartilage ulceration of the medial femoral condyle. In sharp contrast, cartilage on the distal aspect of the femoral condyle of the unstable knee was grossly normal in 2 doxy-treated dogs, and exhibited only thinning andlor surface irregularity in the others. Degenerative cartilage lesions on the medial trochlear ridge, superficial fibrillation of the medial tibia1 plateau, and osteophytosis were, however, unaffected by doxy treatment. Collagenolytic activity and gelatinolytic activity in cartilage extracts from OA knees of untreated dogs were 5-fold and 4-fold greater, respectively, than in extracts from dogs given doxy.Conclusion. Prophylactic administration of doxy markedly reduced the severity of OA in weight-bearing regions of the medial femoral condyle. It remains to be determined whether administration of doxy after OA changes have developed is also effective.Tetracyclines inhibit the activity of neutral matrix metalloproteinases (MMPs) (1-3). This effect has been believed to be due, at least in part, to chelation of zinc and/or calcium (1,4), which maintain the normal structural conformation and hydrolytic activity of the MMPs (5).In osteoarthritis (OA), the activities of MMP-1 (collagenase), MMP-2 (gelatinase), and MMP-3 (stromelysin) in the degenerating cartilage are increased (6-8). We recently showed that doxycycline (doxy), in a concentration approximating that found in human serum after a 200-mg oral dose, inhibited type XI collagenolytic activity in homogenates of human OA cartilage (9). Doxy similarly inhibited the activity of purified kidney epithelial cell gelatinase, a metalloproteinase that yields digestion products from type XI collagen identical to those produced by the OA cartilage homogenates (9). In both cases, we showed that the inhibition could be overcome by addition of excess zinc or calcium. We now present evidence that oral administration of doxy ameliorates cartilage destruction in a canine model of experimentally induced OA.

We calculated mean peak vertical forces (MF,) of each limb of 9 adult mongrel dogs before and 2 weeks, 6 weeks, and 12 weeks after left anterior cruciate ligament transection (ACLT). Five additional dogs were studied before and 2 weeks and 6 weeks after sham ACLT. The gaits of 3 dogs that had undergone ACLT 2.5 years previously were also analyzed. Preoperatively, there were no differences in the MF, of the right and left hind limbs of the 9 dogs; we found that each limb exerted approximately 70% of the dog's static body weight on the force plate. Two weeks following ACLT, the MF, of the operated limbs decreased to 25% of the static body weight, while at 6 weeks and 12 weeks after surgery, the MF, generated by the operated limbs rose to about 32% and 37% of static body weight, respectively. No change was noted in the MF, of the contralateral hind limbs. In the 3 dogs that had undergone ACLT 2.5 years earlier, the MF, in the unstable stifle joint was 50% of static body weight. At both 2 weeks and 6 weeks after surgery, Unilateral transection of the anterior cruciate ligament (ACLT) in the dog induces osteophyte formation and biochemical, metabolic, morphologic, and biomechanical changes in the articular cartilage of the ipsilateral stifle joint that are consistent with those of osteoarthritis (1-5). The rate of development of these changes, and their severity at any given time after ACLT, however, can vary markedly from animal to animal, even when the dogs are maintained at apparently comparable levels of activity (1). It seems reasonable to suspect that the load borne by the unstable limb influences the rate at which the lesions develop. Moreover, it has been shown that articular cartilage from the contralateral stifle joint of dogs subjected to ACLT is characterized by increased water content, increased molar ratios of galactosamine to glucosamine, and an increase in the extractability of matrix proteoglycans (4), as well as diminished proteoglycan aggregation (Brandt KD: unpublished observations).

The presence of nerve fibers and mechanoreceptors in the sacroiliac ligament demonstrates that the central nervous system receives information, certainly proprioceptive, and possibly pain from the sacroiliac joint. Although it is not known how the central nervous system uses such information, it seems reasonable to speculate that the proprioceptive information is used to optimize upper body balance at this joint. In addition, because the staining techniques used generally to show nerves and nerve elements in periarticular connective tissue are nonspecific, the distinction between neural and nonneural should be made on the basis of both morphologic and staining characteristics.

Anterior cruciate ligament transection (ACLT) in the dog produces changes in the articular cartilage of the unstable knee that are consistent with those of osteoarthritis (OA). To determine whether the degrees of severity of OA cartilage changes, of synovitis, and of synovial iron deposition were related to adequacy of hemostasis at the time of ACLT, a modified surgical technique was devised, whereby electrocautery was used to obtain meticulous control of bleeding when the ligament was severed and irrigation was used to remove intraarticular blood before closure of the joint. When no particular attention was given to hemostasis, 69% of the dogs showed synovitis in the OA knee 10 weeks after ACLT; when electrocautery and irrigation were used to maintain hemostasis, synovitis was present in only 24% of the OA knees 10 weeks after ACLT (P < 0.01). Ironl deposits were present in 75% of synovial samples obtained after routine ACLT, but in only 6% (P < 0.001) when attention was given to hemostasis. Hypertrophy of articular cartilage, chondrocyte cloning, fibrillation, and changes in tangential zone chondrocytes were less prominent in the OA knee when electrocautery and irrigation were used. However, the water content, uronic acid concentration, and rate of net 35S-labeled glycosaminoglycan synthesis were similarly increased regardless of the surgical technique used, and presumably, these changes reflect the reaction of joint cartilage to mechanical instability in this model of OA.Anterior cruciate ligament transection (ACLT) in the dog produces a mechanically unstable stifle joint whose articular cartilage develops biochemical, metabolic, and histologic changes that mimic those of osteoarthritis (OA) in humans (1-3). The synovium from the OA joint shows a variable amount of inflammation, with mononuclear cell infiltration, lining cell hyperplasia, and fibrosis (4-7). In contrast, no cartilage abnormalities and only transient synovitis are seen in "sham operated" joints, in which the cruciate ligament is visualized but not cut (43).Although this experimental model of OA has been used in many laboratories, the severity of the pathologic changes has varied (3,8). The basis for such variability is unclear, but could be related to such factors as the animal's age, weight, or breed, the postoperative exercise regimen, or the length of time from surgery to death of the animal (8).One additional variable is the surgical procedure itself. In some cases, the anterior cruciate ligament is transected by a blind stab incision with a