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

Loeser, Richard F.; Shanker, Gouri; Carlson, Cathy S.; Gardin, Jean F.; Shelton, Brent J.; Sonntag, William E.

doi:10.1002/1529-0131(200009)43:9<2110::aid-anr23>3.0.co;2-u

Cited by 177 publications

(124 citation statements)

References 39 publications

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“…These data support previous work that demonstrates what has been coined a resistance to IGF-1 stimulation with age (14)(15)(16)48). Hsp90 inhibition at the 2 higher concentrations of geldanamycin tested (100 nM and 500 nM) blocked IGF-1-induced COL2A1 expression.…”

Section: Discussionsupporting

confidence: 90%

“…In the present study, the oldest chondrocytes (mature) had the greatest Hsp90 AS A THERAPEUTIC TARGET FOR DIMINISHED CARTILAGE CATABOLISM IN OAincrease in COL2A1 mRNA expression after exposure to IGF-1. Previous studies suggesting that chondrocytes become nonresponsive to IGF-1 during aging demonstrated significantly less sulfate incorporation into proteoglycans in aged compared with young chondrocytes (15,16). Taken together, these results suggest that either the IGF-1 nonresponsive state is more specific for proteoglycan than collagen synthesis, or that mRNA expression is less sensitive to the effects of aging than to protein synthesis and assembly of the ECM.…”

Section: Discussionmentioning

confidence: 50%

“…These changes result from decreased mitotic and synthetic activity and diminished responsiveness of chondrocytes to anabolic growth factors, including insulin-like growth factor 1 (IGF-1) (14)(15)(16)(17). One well-known pathway of IGF-1 signaling is through phosphorylation and activation of the protein kinase Akt, which requires binding to Hsp90 for activation (18,19).…”

mentioning

confidence: 99%

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Hsp90 mediates insulin‐like growth factor 1 and interleukin‐1β signaling in an age‐dependent manner in equine articular chondrocytes

Boehm¹,

Seth²,

Mayr³

et al. 2007

Arthritis & Rheumatism

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Objective. Many metabolic processes in chondrocytes thought to contribute to age-related changes in the extracellular matrix are influenced by known roles of Hsp90. Age-related decreases in the level of Hsp90 have been documented in numerous cell types and could contribute to cartilage degeneration. The aim of this study was to investigate the roles of age and Hsp90 in insulin-like growth factor 1 (IGF-1) and interleukin-1␤ (IL-1␤) signaling in chondrocytes.Methods. Levels of Hsp90 messenger RNA (mRNA) and protein, with respect to age, were determined by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. The Hsp90 inhibitor geldanamycin (50 nM, 100 nM, or 500 nM) was used to assess age-related responses to Hsp90 with concurrent IGF-1 or IL-1␤ stimulation of chondrocytes. Quantitative real-time PCR was used to measure COL2A1 and matrix metalloproteinase 13 (MMP13) gene expression; Western blot analysis was performed to determine the phosphorylation status of p42/44 and Akt/protein kinase B.Results. The effects of Hsp90 inhibition with geldanamycin were concentration dependent. Inhibition of Hsp90 with 100 nM or 500 nM geldanamycin blocked IGF-1-induced cell proliferation, Akt and p42/44 activation, and COL2A1 expression. Basal and IL-1␤-induced up-regulation of MMP13 mRNA was blocked by all concentrations of geldanamycin tested. Gain-offunction assays with Hsp90 resulted in increased expression of MMP13 mRNA.Conclusion. These results suggest that Hsp90 is involved in opposing signaling pathways of cartilage homeostasis, and that catabolic responses are more sensitive to Hsp90 inhibition than are anabolic responses. Further studies are needed to determine the role of Hsp90 inhibition in osteoarthritis in order to assess its potential as a therapeutic target.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 50%

mentioning

confidence: 99%

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Hsp90 mediates insulin‐like growth factor 1 and interleukin‐1β signaling in an age‐dependent manner in equine articular chondrocytes

Boehm¹,

Seth²,

Mayr³

et al. 2007

Arthritis & Rheumatism

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“…Midcoronal sections of the distal femur and proximal tibia were examined. To quantify the degree of OA-like change, toluidine blue-stained sections were scored (0-7 scale, where 0 ϭ normal and 7 ϭ severe damage, as previously described [18]) by a single investigator (CSC) who was blinded to the immunostaining results. The sections used for the study had scores ranging from 0 to 7 (mean 2.2).…”

Section: Methodsmentioning

confidence: 99%

Articular chondrocytes express the receptor for advanced glycation end products: Potential role in osteoarthritis

Loeser

Yammani

Carlson

et al. 2005

Arthritis & Rheumatism

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210

180

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Objective. The receptor for advanced glycation end products (RAGE) binds multiple ligands, including S100 proteins, high mobility group box chromosomal protein 1 (HMGB-1), and AGEs, all of which are present in articular cartilage. Stimulation of RAGE signaling can lead to MAP kinase activation and increased NF-B activity. The objective of the present study was to determine if chondrocytes express functional RAGE.Methods. The presence of chondrocyte RAGE was analyzed by immunohistochemistry using normal and osteoarthritic (OA) cartilage from young and old monkeys and humans, immunoblotting of chondrocyte lysates and human cartilage extracts, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA from chondrocytes treated with interleukin-1 (IL-1) and fibronectin fragments. RAGE signaling was evaluated by stimulating chondrocytes with S100B and HMGB-1 and analyzing for activation of the ERK MAP kinase and NF-B. The ability of S100B and HMGB-1 to stimulate matrix metalloproteinase 13 (MMP-13) production was also assessed. A pull-down assay using biotin-labeled S100B was used to demonstrate binding to RAGE.Results. RAGE was detected in sections of monkey knee cartilage and human knee and ankle cartilage. Increased immunostaining for RAGE was noted in cartilage from older adult monkeys and humans and was further increased in OA tissue. RAGE was also detected by immunoblotting and by RT-PCR, where IL-1␤ and fibronectin fragments were found to stimulate RAGE expression. Stimulation of chondrocytes with S100B or HMGB-1 increased phosphorylation of the ERK MAP kinase and the p65 subunit of NF-B and increased the production of MMP-13. This signaling was inhibited in cells pretreated with soluble RAGE, and S100B was shown to bind to chondrocyte RAGE.Conclusion. Articular chondrocytes express functional RAGE. The increase in RAGE noted in OA cartilage and the ability of RAGE ligands to stimulate chondrocyte MAP kinase and NF-B activity and to stimulate MMP-13 production suggests that chondrocyte RAGE signaling could play a role in OA.

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“…In contrast, Verbruggen et al [38] did not observe any proliferation for 2-to 69-year-old human chondrocytes embedded in agarose, but an increase in donor age correlated with reduced aggrecan synthetic rate and a smaller proportion of large aggregates. Loeser et al [26], by measuring sulfate and proline incorporation in alginate culture, found a mitigated response of macaque chondrocytes to IGF-1 with increasing animal age. Kamada et al [23] observed that primary aged bovine chondrocytes in alginate proliferate less than chondrocytes from young adults, but nonetheless more than fetal chondrocytes.…”

Section: Introductionmentioning

confidence: 99%

Aged bovine chondrocytes display a diminished capacity to produce a collagen-rich, mechanically functional cartilage extracellular matrix

et al. 2005

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Most fundamental studies in cartilage tissue engineering investigate the ability of chondrocytes from young animals to produce cartilaginous matrix under various conditions, while current clinical applications such as autologous chondrocyte implantation, use chondrocytes from donors that are decades past skeletal maturity. Previous investigations have suggested that several characteristics of primary chondrocytes are age-dependent but none have quantified cell proliferation, proteoglycan synthesis and accumulation, collagen synthesis and accumulation, compressive and tensile mechanical properties in order to examine the effects of donor age on all of these parameters. We enzymatically isolated primary bovine chondrocytes from fetal, young and aged animals and cultured these cells in agarose gels to assess the above-mentioned properties. We found that fetal and young (but still skeletally mature i.e. 18-month-old bovine) chondrocytes behaved similarly, while aged chondrocytes (5-to 7-year-old bovine) displayed diminished proliferation (-2x less), a slightly reduced proteoglycan accumulation per cell (-20%), and significantly less collagen accumulation per cell (-55%) compared to the younger cells. Histological observations and mechanical properties supported these findings, where a particularly significant reduction in tensile stiffness produced by aged chondrocytes compared to younger cells was observed. Our findings suggest that donor age is an important factor in determining the outcome and potential success when tissue-engineered cartilage is produced from articular chondrocytes. More specifically, primary chondrocytes from aged donors may not possess sufficient capacity to produce the extracellular matrix that is required for a mechanically resilient tissue.

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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

Cited by 177 publications

References 39 publications

Hsp90 mediates insulin‐like growth factor 1 and interleukin‐1β signaling in an age‐dependent manner in equine articular chondrocytes

Hsp90 mediates insulin‐like growth factor 1 and interleukin‐1β signaling in an age‐dependent manner in equine articular chondrocytes

Articular chondrocytes express the receptor for advanced glycation end products: Potential role in osteoarthritis

Aged bovine chondrocytes display a diminished capacity to produce a collagen-rich, mechanically functional cartilage extracellular matrix

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