Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis - Studies in a non-human primate model of naturallyoccurring disease
Rf. Loeser et al., Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis - Studies in a non-human primate model of naturallyoccurring disease, ARTH RHEUM, 43(9), 2000, pp. 2110-2120
Objective. Although the development of osteoarthritis (OA) is closely assoc
iated with aging, the mechanism for this association is not clear. This stu
dy 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 m
onkeys at the time of necropsy. Each joint site was scored histologically o
n a scale of 0-7 for OA pathologic changes. Isolated chondrocytes were cult
ured 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) th
an IGF-1. Response was measured as the ability to stimulate sulfate and pro
line 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 s
ignificant decline in the response to IGF-1 was noted with both increasing
age and increasing OA score. Controlling for the OA score, the estimated ef
fect 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 a
s 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 H-3-proline-labele
d 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 d
es(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-l
suggests a role of increased production of inhibitory IGFBP in OA. Since th
e cells from older animals had a reduced response to both forms of IGF-1, t
he mechanism of the reduced response with age cannot be attributed to chang
es in IGFBP. Age-related changes in IGF receptors or, more likely, age-rela
ted alterations in intracellular signal transduction may also be involved.