Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease.

OBJECTIVE: Although the development of osteoarthritis (OA) is closely associated with aging, the mechanism for this association is not clear. This study was designed to determine the effects of aging and OA on the chondrocyte response to stimulation with insulin-like growth factor 1 (IGF-1) in a non-human primate model of naturally occurring OA. METHODS: Chondrocytes were isolated from cartilage removed separately from the medial and lateral femoral condyles and tibial plateaus of cynomolgus monkeys at the time of necropsy. Each joint site was scored histologically on a scale of 0-7 for OA pathologic changes. Isolated chondrocytes were cultured in alginate in serum-free medium and stimulated with IGF-1 or des(1-3) IGF-1, which has a much lower affinity for IGF binding proteins (IGFBP) than IGF-1. Response was measured as the ability to stimulate sulfate and proline incorporation. RESULTS: Cartilage samples from 34 monkeys ranging in age from 6.7 years to 27 years and with histologic scores ranging from 0 to 7 were analyzed. A significant decline in the response to IGF-1 was noted with both increasing age and increasing OA score. Controlling for the OA score, the estimated effect of age on IGF-1 response, measured by total sulfate incorporation, was a decline of 3.81% per year (P = 0.0001), or a 75% decline over 20 years as a monkey ages from young to older adult. Controlling for age, the effect of OA score was significant only for proline incorporation in the alginate matrix (estimated slope coefficient +/-standard error -15.9 +/- 7.2; P = 0.03), suggesting a negative effect of OA on retention of 3H-proline-labeled proteins in the matrix. There was a significantly reduced response to des(1-3) IGF-1 with increasing age, but no effect of OA score on response to des(1-3) IGF-1. There was no effect of age on cell viability. CONCLUSION: These results demonstrate a significant age-related decline in the chondrocyte response to IGF-1. The finding that increasing OA score was associated with a reduced response to intact IGF-1 but not des(1-3) IGF-1 suggests a role of increased production of inhibitory IGFBP in OA. Since the cells from older animals had a reduced response to both forms of IGF-1, the mechanism of the reduced response with age cannot be attributed to changes in IGFBP. Age-related changes in IGF receptors or, more likely, age-related alterations in intracellular signal transduction may also be involved.

Osteoarthritis in cynomolgus macaques. III: Effects of age, gender, and subchondral bone thickness on the severity of disease.

Knee joints from cynomolgus monkeys of both genders and a wide range of ages were examined to characterize further the natural history of osteoarthritis (OA) in these animals. The objectives of this study were to characterize better the subchondral bone changes previously noted in this disease, to determine whether the severity of OA in these animals is affected by age or weight, and to determine whether males and females are affected similarly. As had been seen in previous studies, the medial tibial plateau was the most severely affected site. The thickness of the subchondral plate in the medial tibial plateau increased with increasing severity of articular cartilage lesions in both males and females; however, in monkeys with subchondral plate thicknesses less than 400 microns, articular cartilage lesions were essentially absent. Subchondral plate thickness increased with increasing weight in both genders, but females had a higher subchondral plate thickness than males for a given body weight. There was no correlation between bone volume in the proximal tibial epiphysis and articular cartilage lesions of OA. The prevalence and severity of OA in the medial tibial plateau increased with increasing age, but were not affected by gender or weight. Although there was no correlation between articular cartilage lesions and body mass index or weight, the waist/hip circumference ratio and severity of articular cartilage lesions were correlated in the female monkeys. This work provides evidence that thickening of the subchondral bone plate may be more important than the volume of epiphyseal/metaphyseal cancellous bone in determining the biomechanical stresses in the joint and in influencing the development of articular cartilage lesions.

Maternal factors affecting reproduction in a breeding colony of cynomolgus macaques (Macaca fascicularis).

A breeding colony of cynomolgus macaques (Macaca fascicularis), composed of imported and colony-born animals and established for 9 years, was evaluated for maternal factors associated with reproductive failure. The factors evaluated included age, gravidity, parity, origin, previous stillbirths, clinical incidents and type of housing. The effects of each factor on pregnancy rate (PR), stillbirth rate (SR), infant mortality rate (IMR) and pregnancy success (PS) were evaluated. The overall colony rates were: PR = 53%, SR = 22%, IMR = 22%, and PS = 60%. Neonatal death rate for the group was 12%. Pregnancy rate was most affected by maternal factors. Clinical incidents occurring during pregnancy were associated with a significant increase in the stillbirth rate, but did not affect infant mortality rate. Maternal age did not affect any of the measures of reproductive output. Pregnancy rate peaked at 6-8 years of age and decreased thereafter, while pregnancy success peaked at 9-11 years of age. Gravidity and parity had a positive linear relationship with pregnancy rate.

Noninvasive assessment of atherosclerosis in nonhuman primates.

Atherosclerosis is a progressive and degenerative disease of the artery wall which begins relatively early in life, years if not decades prior to the onset of clinical signs and symptoms. One of the major challenges which face investigators in this field of research is to establish the validity and reliability of noninvasive methods which can detect atherosclerotic plaques before they become severe enough to result in tissue ischemia, and to determine whether or not atherosclerotic lesions can be monitored both in terms of rate and direction over time. Although several methods of direct arterial visualization are available currently, high-resolution B-mode ultrasound imaging appears to have the most advantages. This technique is noninvasive, relatively inexpensive, and can visualize not only lumen contour and configuration, but also the atherosclerotic plaque in the underlying wall. Preliminary experiments in animal models suggest that lesions as small as 0.5 mm in the carotid arteries can be detected using this method. Whether or not atherosclerotic plaques can be monitored over time, however, has not been demonstrated.