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Objective—To assess the effects of supraphysiologic concentrations of insulin-like growth factor-I (IGF-1) on morphologic and phenotypic responses of chondrocytes.
Sample Population—Articular cartilage obtained from 2 young horses.
Procedure—Chondrocytes were suspended in fibrin cultures and supplemented with 25, 12.5, or 0 mg of IGF-1/ml of fibrin. Chondrocyte morphology and phenotypic expression were assessed histologically, using H&E and Alcian blue stains, immunoreaction to collagen type I and II, and in situ hybridization. Proteoglycan content, synthesis, and monomer size were analyzed. The DNA content was determined by bisbenzimide-fluorometric assay, and elution of IGF-1 into medium was determined by IGF-1 radioimmunoassay.
Results—Both 12.5 and 25 µg of IGF-1/ml enhanced phenotypic expression of chondrocytes without inducing detrimental cellular or metabolic effects. Highest concentration of IGF-1 (25 µg/ml) significantly increased total DNA content, glycosaminoglycan (GAG) content, GAG synthesis, and size of proteoglycan monomers produced, compared with cultures supplemented with 12.5 µg of IGF-1/ml or untreated cultures. Histologic examination confirmed these biochemical effects. Matrix metachromasia, type-II collagen in situ hybridization and immunoreaction were increased in cultures treated with 25 µg of IGF-1/ml, compared with cultures supplemented with 12.5 µg of IGF-1/ml or untreated cultures.
Conclusions and Clinical Relevance—Chondrocytes exposed to high concentrations of IGF-1 maintained differentiated chondrocyte morphology and had enhanced synthesis of matrix molecules without inducing apparent detrimental effects on chondrocyte metabolism. These results suggest that application of such composites for in vivo use during cartilage grafting procedures should provide an anabolic effect on the grafted cells. (Am J Vet Res 2002;63:301–305)
Objective—To determine whether abnormal laxity of hip joints of canine pups with genetic predisposition to hip dysplasia (HD+) is related to ingestion of milk-borne hormones.
Animals—7 female Labrador Retrievers with HD+ and 8 with low predisposition to hip dysplasia (HD–) and their offspring.
Procedures—Immunoactive relaxin, estrogen, and estrogen precursor concentrations in milk of HD+ lactating bitches and in serum of their pups were compared with those of HD– bitches and pups. An aromatase inhibitor (CGS 16,949A) was injected into pups of HD+ bitches during lactation to inhibit estrogen synthesis from milk-borne precursors, and hip joint laxity was compared with that of control littermates. Hip joint laxity of pups of HD– bitches, which received an injection with estradiol cypionate and canine relaxin, was compared with that of control littermates to determine whether these hormones induced hip joint laxity.
Results—High concentrations of estrogens and relaxin were found in milk of HD+ and HD– bitches throughout lactation. Serum concentrations of milk-derived relaxin and total estrogens were similar in all pups, but estradiol-17B was detected only in pups of HD+ bitches. Hip joint laxity was reduced in pups that received CGS 16,949A. Hip joint laxity was increased in pups of HD– bitches that received estradiol cypionate and relaxin.
Conclusions and Clinical Relevance—Milk-borne maternal hormones and precursors were absorbed into the circulation of canine neonates and may play a role in hip joint laxity in HD+ pups. Phenotypic expression of hip dysplasia may therefore be preventable by antihormone treatment.
Objective—To determine prevalence of radiographic evidence of osteoarthritis in 4 diarthrodial joints of dogs with restricted feed intake, compared with dogs without restricted feed intake.
Design—Paired feeding study.
Animals—48 Labrador Retrievers.
Procedure—Dogs in litters from 7 dams and 2 sires were paired by sex and weight within litters and randomly assigned to a control-fed group or a limit-fed group that received 25% less food than the controlfed group. Radiographic evaluation of prevalence and severity of osteoarthritis in the hip, shoulder, elbow, and stifle joints was performed when dogs were 8 years of age.
Results—Radiographic evidence of osteoarthritis that affected multiple joints was significantly more common in the control-fed group than in the limit-fed group. Prevalence of lesions in the hip joint was 15/22 in the control-fed group and 3/21 in the limit-fed group. Prevalence of lesions in the shoulder joint was 19/22 in the control-fed group and 12/21 in the limitfed group; lesions in this joint were generally mild. Severity, but not prevalence, of osteoarthritis in the elbow joint was greater in the control-fed group than in the limit-fed group.
Conclusions and Clinical Relevance—Prevalence and severity of osteoarthritis in several joints was less in dogs with long-term reduced food intake, compared with control dogs. Food intake is an environmental factor that may have a profound effect on development of osteoarthritis in dogs. (J Am Vet Med Assoc 2000;217:1678–1680)
Objective—To compare the bone mineral density (BMD) of the proximal portion of the femur in dogs with and without early osteoarthritis secondary to hip dysplasia.
Animals—24 dogs (3 Greyhounds, 6 Labrador-Greyhound crossbreeds, and 15 Labrador Retrievers).
Procedure—Computed tomography (CT) of the pelvis, including a bone-density phantom, was performed for each dog. Centrally located transverse CT slices and a computer workstation were used to identify 16 regions of interest (ROIs) in the proximal portion of the femur. For each ROI, the mean Hounsfield unit value was recorded; by use of the bone-density phantom and linear regression analysis, those values were converted to equivalent BMD (eBMD). Mean eBMD values for the subchondral and nonsubchondral ROIs in dogs with and without osteoarthritis (determined at necropsy) were compared. A mixed-model ANOVA and post hoc linear contrasts were used to evaluate the effects of osteoarthritis, breed, and sex on the BMD value.
Results—At necropsy, osteoarthritis was detected in 14 hip joints in 9 dogs; all lesions included early cartilage fibrillation. After adjusting for breed and sex, eBMD in subchondral ROIs 8 and 12 (adjacent to the fovea) were 8% and 6% higher, respectively, in osteoarthritis-affected dogs, compared with unaffected dogs; in the nonsubchondral ROIs, eBMD was 10% higher in osteoarthritis-affected dogs.
Conclusions and Clinical Relevance—Compared with findings in unaffected dogs, increased eBMD in hip joints of dogs with early osteoarthritis supports a strong relationship between the subchondral and epiphyseal regions and articular cartilage in the pathogenesis and progression of osteoarthritis.
Objective—To evaluate the quantitative inheritance of secondary hip joint osteoarthritis in a canine pedigree.
Animals—137 Labrador Retrievers, Greyhounds, and mixed-breed dogs.
Procedures—Necropsy scores ranging from 0 to 4 were obtained for each hip joint. Seven unaffected Greyhounds with normal hip joint conformation were also used for genetic modeling, but were not euthanized. Sixty-six male and 71 female dogs were allocated to 2 groups (≤ 12 months of age and > 12 months of age). Statistical models were developed to establish the inheritance pattern of hip joint osteoarthritis that developed secondary to hip dysplasia.
Results—62 dogs had evidence of osteoarthritis in a hip joint, and 75 had no evidence of osteoarthritis. After sex was adjusted for, the necropsy score was found to be inherited additively but without dominance. Each Labrador Retriever allele increased the necropsy score by 0.7 to 0.9 points, compared with the Greyhound allele, and male sex increased the necropsy score 0.74 over female sex. Approximately 10% of the variation in necropsy score was attributable to the litter of puppies' origin.
Conclusions and Clinical Relevance—Because secondary hip joint osteoarthritis is inherited additively, selection pressure could be applied to reduce its incidence. Similar statistical models can be used in linkage and association mapping to detect the genes in the underlying quantitative trait loci that contribute to hip joint osteoarthritis.
Objective—To determine whether dorsolateral subluxation (DLS) scores in young dogs could be used to reliably predict which dogs would develop evidence of hip osteoarthritis and whether DLS scores measured at various ages correlated with each other.
Animals—129 Labrador Retrievers, Greyhounds, and Labrador Retriever-Greyhound crossbreds.
Procedures—DLS scores were measured on radiographs taken at 4, 8, and 12 months of age and at necropsy (8 to 36 months of age). At necropsy, the hip joints were examined macroscopically and a score assigned for degree of cartilage degeneration.
Results—DLS scores at 4 (n = 35, r s = –0.62), 8 (n = 106, r s = –0.54), and 12 (n = 15, r s = –0.87) months of age were significantly correlated with cartilage degeneration scores, and DLS scores at 8 months of age were significantly correlated with scores obtained at the time of necropsy (n = 39, r s = 0.87). The DLS scores at 4 months of age were significantly different from scores at 8 months of age, but scores did not differ significantly thereafter. Likelihood ratios for cartilage lesions for low (< 45%), intermediate (≥ 45 but ≤ 55%), and high (> 55%) DLS scores at 8 months of age were 8.0, 2.6, and 0.2, respectively.
Conclusions and Clinical Relevance—Results suggest that DLS score at 8 months of age was a reasonable, albeit imperfect, predictor of the condition of the hip joint cartilage at necropsy. Thus, the DLS method might be useful for early identification of dogs with hip dysplasia. (Am J Vet Res 2001;62:1711–1715)
Objective—To determine the genetic influence on expression of traits associated with canine hip dysplasia.
Animals—193 dogs from an experimental canine pedigree.
Procedure—An experimental canine pedigree was developed for linkage analysis of hip dysplasia by mating dysplastic Labrador Retrievers with nondysplastic Greyhounds. A statistical model was designed to test the effects of Labrador Retriever and Greyhound alleles on age at detection of femoral capital epiphyseal ossification, 8-month distraction index, and 8-month dorsolateral subluxation score.
Results—The additive effect was significant for age at detection of femoral capital epiphyseal ossification. Restricted maximum likelihood estimates (± SD) for this trait were 6.4 ± 1.95, 10.2 ± 2.0, 10.8 ± 3.1, 11.4 ± 2.1, and 13.6 ± 4.6 days of age for Greyhounds, Greyhound backcross dogs, F1 dogs, Labrador Retriever backcross dogs, and Labrador Retrievers, respectively. The additive effect was also significant for the distraction index. Estimates for this trait were 0.21 ± 0.07, 0.29 ± 0.15, 0.44 ± 0.12, 0.52 ± 0.18, and 0.6 ± 0.17 for the same groups, respectively. For the dorsolateral subluxation score, additive and dominance effects were significant. Estimates for this trait were 73.5 ± 4.1, 71.3 ± 6.5, 69.1 ± 6.0, 50.6 ± 12.9, and 48.4 ± 7.7%, respectively, for the same groups.
Conclusions—In this canine pedigree, traits associated with canine hip dysplasia are heritable. Phenotypic differences exist among founder dogs of each breed and their crosses. This pedigree should be useful for identification of quantitative trait loci underlying the dysplastic phenotype. (Am J Vet Res 2002;63: 1029–1035)
Objective—To estimate the number of dogs required to find linkage to heritable traits of hip dysplasia in dogs from an experimental pedigree.
Animals—147 Labrador Retrievers, Greyhounds, and their crossbreed offspring.
Procedure—Labrador Retrievers with hip dysplasia were crossed with unaffected Greyhounds. Age at detection of femoral capital ossification, distraction index (DI), hip joint dorsolateral subluxation (DLS) score, and hip joint osteoarthritis (OA) were recorded. Power to find linkage of a single marker to a quantitative trait locus (QTL) controlling 100% of the variation in a dysplastic trait in the backcross dogs was determined.
Results—For the DI at the observed effect size, recombination fraction of 0.05, and heterozygosity of 0.75, 35 dogs in the backcross of the F1 to the Greyhound generation would yield linkage at a power of 0.8. For the DLS score, 35 dogs in the backcross to the Labrador Retriever generation would be required for linkage at the same power. For OSS, 45 dogs in the backcross to the founding Labrador Retrievers would yield linkage at the same power. Fewer dogs were projected to be necessary to find linkage to hip OA. Testing for linkage to the DLS at 4 loci simultaneously, each controlling 25% of the phenotypic variation, yielded an overall power of 0.7.
Conclusions and Clinical Significance—Based on this conservative single-marker estimate, this pedigree has the requisite power to find microsatellites linked to susceptibility loci for hip dysplasia and hip OA by breeding a reasonable number of backcross dogs. (Am J Vet Res 2003;222:418–424)
Objective—To determine the radiographic methods that best predict the development of osteoarthritis in the hip joints of a cohort of dogs with hip dysplasia and unaffected dogs.
Animals—205 Labrador Retrievers, Greyhounds, and Labrador Retriever-Greyhound crossbred dogs.
Procedure—Pelvic radiography was performed when the dogs were 8 months old. Ventrodorsal extendedhip, distraction, and dorsolateral subluxation (DLS) radiographs were obtained. An Orthopedic Foundation for Animals-like hip score, distraction index, dorsolateral subluxation score, and Norberg angle were derived from examination of radiographs. Osteoarthritis was diagnosed at the time of necropsy in dogs ≥ 8 months of age on the basis of detection of articular cartilage lesions. Multiple logistic regression was used to determine the radiographic technique or techniques that best predicted development of osteoarthritis.
Results—A combination of 2 radiographic methods was better than any single method in predicting a cartilage lesion or a normal joint, but adding a third radiographic method did not improve that prediction. A combination of the DLS score and Norberg angle best predicted osteoarthritis of the hip joint or an unaffected hip joint. All models that excluded the DLS score were inferior to those that included it.
Conclusions and Clinical Relevance—A combination of the DLS score and Norberg angle was the best predictor of radiographic measures in 8-month-old dogs to determine whether a dog would have normal or osteoarthritic hip joints. (Am J Vet Res 2003;64:1472–1478)
Objective—To identify quantitative trait loci (QTL) associated with osteoarthritis (OA) of hip joints of dogs by use of a whole-genome microsatellite scan.
Animals—116 founder, backcross, F1, and F2 dogs from a crossbred pedigree.
Procedures—Necropsy scores and an optimized set of 342 microsatellite markers were used for interval mapping by means of a combined backcross and F2 design module from an online statistical program. Breed and sex were included in the model as fixed effects. Age of dog at necropsy and body weight at 8 months of age were also included in the model as covariates. The chromosomal location at which the highest F score was obtained was considered the best estimate of a QTL position. Chromosome-wide significance thresholds were determined empirically from 10,000 permutations of marker genotypes.
Results—4 chromosomes contained putative QTL for OA of hip joints in dogs at the 5% chromosome-wide significance threshold: chromosomes 5, 18, 23, and 31.
Conclusions and Clinical Relevance—Osteoarthritis of canine hip joints is a complex disease to which many genes and environmental factors contribute. Identification of contributing QTL is a strategy to elucidate the genetic mechanisms that underlie this disease. Refinement of the putative QTL and subsequent candidate gene studies are needed to identify the genes involved in the disease process.