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Abstract

Osteoarthritis (OA) is a common joint disease, mainly effecting the elderly population. The cause of OA seems to be an imbalance in catabolic and anabolic factors that develops with age. IL-1 is a catabolic factor known to induce cartilage damage, and transforming growth factor (TGF)-beta is an anabolic factor that can counteract many IL-1-induced effects. In old mice, we observed reduced responsiveness to TGF-beta-induced IL-1 counteraction. We investigated whether expression of TGF-beta and its signaling molecules altered with age. To mimic the TGFbeta deprived conditions in aged mice, we assessed the functional consequence of TGF-beta blocking. We isolated knee joints of mice aged 5 months or 2 years, half of which were exposed to IL-1 by intra-articular injection 24 h prior to knee joint isolation. Immunohistochemistry was performed, staining for TGF-beta1, -2 or -3, TGF-betaRI or -RII, Smad2, -3, -4, -6 and -7 and Smad-2P. The percentage of cells staining positive was determined in tibial cartilage. To mimic the lack of TGF-beta signaling in old mice, young mice were injected with IL-1 and after 2 days Ad-LAP (TGF-beta inhibitor) or a control virus were injected. Proteoglycan (PG) synthesis ( 35 S-sulfate incorporation) and PG content of the cartilage were determined. Our experiments revealed that TGF-beta2 and -3 expression decreased with age, as did the TGF-beta receptors. Although the number of cells positive for the Smad proteins was not altered, the number of cells expressing Smad2P strongly dropped in old mice. IL-1 did not alter the expression patterns. We mimicked the lack of TGF-beta signaling in old mice by TGFbeta inhibition with LAP. This resulted in a reduced level of PG synthesis and aggravation of PG depletion. The limited response of old mice to TGF-beta induced-IL-1 counteraction is not due to a diminished level of intracellular signaling molecules or an upregulation of intracellular inhibitors, but is likely due to an intrinsic absence of sufficient TGF-beta receptor expression. Blocking TGF-beta distorted the natural repair response after IL-1 injection. In conclusion, TGF-beta appears to play an important role in repair of cartilage and a lack of TGF-beta responsiveness in old mice might be at the root of OA development.

Epigenomic Profiling of Young and Aged HSCs Reveals Concerted Changes during Aging that Reinforce Self-Renewal

“…While decreased TGF-β signaling has been implicated in aging of cardiac and neural tissue (Blaney Davidson et al, 2005; Loffredo et al, 2013), here we observed genes involved in specific signaling modules that are likely mediating the altered TGF-β response. In the context of the HSC, we are inferring responses to stimuli that are likely initiated by the niche based on the large number of dysregulated TGF-β genes.…”

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

“…Chondrocyte proteoglycan synthesis has been reported to decline with age in response to the related BMP family members BMP-6 (30) and TGFβ (31) but OP-1 had not been previously studied. We did observe that induction of oxidative stress using tBHP inhibited OP-1 stimulated proteoglycan synthesis.…”

The Role of Changes in Extracellular Matrix of Cartilage in the Presence of Inflammation on the Pathology of Osteoarthritis

“…Concurrently with matrix degradation, the inflammation-mediated downregulation of chondrogenic growth/transcription factors that mediate chondrocytic ECM synthesis, such as transforming growth factor β (TGF- β ), sex determining region Y-box 9 (SOX9), insulin-like growth factor (IGF), and connective tissue growth factor (CTGF), is also responsible for suppressing the anabolic activities of chondrocytes [1, 37, 38]. Taken together, these results demonstrate the significant influence of inflammatory mediators in the progression of OA by altering the homeostasis of cartilage ECM.…”