Transforming Growth Factor-β is Most Associated with Keloid Formation

The growth factor most strongly associated with keloid formation is transforming growth factor-β (TGF-β). 1

Mechanism of TGF-β in Keloid Formation

TGF-β plays a critical role in keloid pathogenesis through its effects on fibroblast proliferation and collagen production 1
Keloid tumors are benign, monoclonal fibroblast tumors characterized by increased collagen production, similar to other fibroproliferative disorders 1
TGF-β promotes increases in extracellular matrix production and decreases collagenase production, leading to excessive collagen accumulation 1

Studies have demonstrated that TGF-β1 and TGF-β2 proteins are expressed at significantly higher levels in keloid fibroblast cultures compared to normal human dermal fibroblast cultures 2
Keloid fibroblasts produce up to 12 times more collagen than normal skin fibroblasts, and show a marked sensitivity to TGF-β stimulation 3
TGF-β1 can increase collagen production in keloid fibroblasts by up to 2.7 times, while neutralizing antibodies against TGF-β reduce collagen synthesis by 40% 3

While there are three TGF-β isoforms (β1, β2, and β3), TGF-β1 and TGF-β2 are particularly implicated as fibrosis-inducing cytokines in keloid formation 2
TGF-β3 expression is comparable between normal and keloid fibroblasts, suggesting it may not play the same pathological role as the other isoforms 2
The TGF-β3 isoform has been found to be elevated in other fibroproliferative disorders like leiomyomas, showing a pattern of dysregulation in fibrotic conditions 1

TGF-β mediates its effects through the Smad signaling pathway, which is crucial for keloid pathogenesis 4
The p38 MAPK pathway significantly affects TGF-β/Smad signal transduction by regulating Smad2/3 phosphorylation, especially at the linker region 4
ERK and JNK pathways also contribute to TGF-β signaling by affecting Smad complex translocation into the nucleus 4

Novel truncated TGF-β receptors (tTGFβRII) can trap TGF-β1, preventing it from accessing wild-type receptors and suppressing TGF-β triggered signals 5
Treatment with tTGFβRII inhibits growth of keloid fibroblasts and suppresses type I collagen synthesis in a concentration-dependent manner 5
Understanding TGF-β's role in keloid formation has led to exploration of targeted therapies that block specific growth factors regulating proliferation and collagen production 1

While other growth factors like PDGF, EGF, bFGF, and TNF-α are involved in wound healing, they don't show the same level of dysregulation in keloids as TGF-β 1
PDGF stimulates chemotaxis and mitogenicity of fibroblasts but doesn't demonstrate the same pathological overexpression in keloids 1
VEGF promotes angiogenesis and vascular permeability but is not specifically implicated in the excessive collagen deposition characteristic of keloids 1