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Among the most important are (i) the TGF- signaling pathway that triggers downstream events such as the expression of connective tissue growth factor (CTGF), (ii) pathological mechanical forces (mechanotransduction) that occur through overload, repetitive stress or injury, (iii) pro-inflammatory cytokines and innate immunity in a persistent inflammatory environment, and (iv) excessive oxidative stress leading to cellular aging and senescence ( Figure 5 ) (90)

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