Aging and Oxidative Stress Reduce the Response of Human Articular Chondrocytes to Insulin‐like Growth Factor 1 and Osteogenic Protein 1

Abstract

Objective A reduced response of articular chondrocytes to growth factors with aging could contribute to the development of osteoarthritis. The purpose of this study was to determine the effects of aging and oxidative stress on the response of human articular chondrocytes to insulin-like growth factor-1 (IGF-1) and osteogenic protein-1 (OP-1). Methods Chondrocytes isolated from normal human articular cartilage obtained from tissue donors were cultured in alginate beads or monolayer. Cells were stimulated with 50–100 ng/ml of IGF-1, OP-1, or both. Oxidative stress was induced using tert-butyl-hydroperoxide. Sulfate incorporation was used to measure proteoglycan synthesis and cell lysates to evaluate signaling proteins by immunoblotting. Confocal microscopy was used to measure nuclear translocation of Smad4. Results Chondrocytes isolated from tissue donors ranging in age from 24 to 81 years demonstrated an age-related decline in IGF-1 and IGF-1+OP-1 stimulated proteoglycan synthesis. Induction of oxidative stress inhibited both IGF-1 and OP-1 stimulated proteoglycan synthesis. Signaling studies revealed oxidative stress inhibited IGF-1 stimulated Akt phosphorylation while increasing phosphorylation of ERK and these effects were greater in cells from older donors. Oxidative stress also increased p38 phosphorylation which resulted in phosphorylation of Smad1 at the Ser206 inhibitory site and reduced Smad1 nuclear accumulation. Oxidative stress also modestly reduced OP-1 stimulated nuclear translocation of Smad4. Conclusion These results demonstrate an age-related reduction in response of human chondrocytes to IGF-1 and OP-1, two important anabolic factors in cartilage, and suggest oxidative stress may be a contributing factor by altering IGF-1 and OP-1 signaling.

Impact of Therapeutic Irradiation on Healthy Articular Cartilage

“…1) (73). Furthermore, recent studies show that oxidative stress can: 1. activate HSP70, a major regulator of chondrocyte homeostasis and inflammation (74); 2. stimulate nuclear protein 1 (Nupr1), involved in gene transcription, which regulates matrix metalloproteinase 13 (MMP-13) expression (75); and 3. increase ERK and p38 phosphorylation (76). These results demonstrate novel regulations of oxidative stress in chondrocytes from articular cartilage.…”

“…These results demonstrate novel regulations of oxidative stress in chondrocytes from articular cartilage. Oxidative stress also inhibits IGF-1-stimulated Akt phosphorylation (76) leading to low Akt activation in stressed chondrocytes. These pathways affect many biological processes, including mitosis, apoptosis and angiogenesis (77).…”

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

“…For these experiments, younger donors were Ͻ50 years old, and older donors were Ն50 years old. The age cut-off for young and old donors was chosen based on a previous study from our group that demonstrated a decline in the response to IGF-1 and altered signaling under conditions of oxidative stress in chondrocytes from donors older than 50 years (27). The average age of younger cartilage was 41.3 Ϯ 6.1 years (range, 36 -48) with a Total Knee Macroscopic Cartilage Score of 57.75 Ϯ 2.8 corresponding to Grade I (minimal changes).…”

“…Disrupted pro-anabolic IGF-1 signaling has been implicated in the pathogenesis of OA, and age-associated reductions in the chondrocyte response to IGF-1 have been associated with oxidative stress (26,27). The aim of this study was to examine whether menadione-induced oxidative stress could promote chondrocyte PRX hyperoxidation in an age-related manner and determine whether this was associated with disrupted IGF-1 signaling, chondrocyte cell death, and osteoarthritis.…”

Effects of Artesunate on the Expressions of Insulin-Like Growth Factor-1, Osteopontin and C-Telopeptides of Type II Collagen in a Rat Model of Osteoarthritis

“…Research has shown that IGF-1 plays an important role in promoting cartilage repairing progress, while OA is mainly characterized by degeneration of cartilage; therefore, increased IGF-1 would help to promote cartilage repair progress [24]. IGF-1 accelerates the differentiation of chondrocytes, stimulates the synthesis of cartilage matrix, and inhibits the matrix decomposition mediated by chondrocytes [25]. IGF-1, its receptor, and IGF-binding proteins together were called as IGF system and act jointly.…”