Fibromodulin

Mechanism of Action

• Binds collagen fibril surface via leucine-rich repeat domain, regulating lateral fibril fusion and controlling fibril diameter during development and repair
• Competes with decorin for overlapping collagen binding sites; fibromodulin and decorin together set the precise collagen fibril architecture of tendon
• Sequesters TGF-beta1 in ECM, limiting pro-fibrotic signaling and scar formation; key anti-fibrotic mechanism
• In wounds: fibromodulin promotes myofibroblast differentiation and collagen cross-linking in ways that result in organized, regenerative repair vs scar
• Stimulates Wnt/beta-catenin in dermal progenitors, promoting re-epithelialization and hair follicle neogenesis in large wounds

Research Findings

• Fibromodulin knockout mice develop tendon and ligament with abnormal collagen fibril ultrastructure (thicker, irregular fibrils) and reduced tensile strength
• Intradermal injection of recombinant fibromodulin into murine full-thickness wounds produced scarless healing with organized collagen, hair follicle and sebaceous gland regeneration
• First-in-human topical fibromodulin gel (rhFMOD) clinical trial: reduced hypertrophic scar formation after reconstructive surgery with acceptable tolerability
• Fibromodulin reduced keloid fibroblast collagen synthesis in vitro and inhibited keloid growth in mouse xenograft models
• Fibromodulin expression is dramatically reduced in hypertrophic scars and keloids vs unwounded skin, suggesting deficiency drives excessive scarring

Research Protocols

• Intradermal injection: 1-10 mcg per wound site in murine full-thickness wound model, administered at wounding or 24 hours post-wounding
• Human scar trial: 0.1-1 mg/mL topical gel applied to surgical incision sites for 14 days post-surgery
• Tendon repair model: 5-50 mcg intratendinous injection after Achilles tendon transection in rats
• In vitro collagen fibril assay: 50-500 nM fibromodulin added to in vitro collagen fibrillogenesis reaction; monitor fibril diameter by TEM

Interactions

• Decorin: overlapping but distinct collagen-binding sites; together regulate fibril diameter homeostasis; decorin-null + fibromodulin-null mice have most severe tendon phenotype
• TGF-beta1/2: fibromodulin sequesters TGF-beta; fibromodulin loss releases TGF-beta and drives fibrotic repair
• Lumican: another keratan sulfate SLRP that regulates collagen fibril assembly in cornea and connective tissue

Safety Profile

Recombinant fibromodulin well tolerated in mouse and first-in-human studies. Topical gel showed no significant local or systemic adverse effects in Phase I/II scar trial. No approved product; advanced clinical development for scar prevention.

Legal & Regulatory

Investigational; Phase I/II clinical trials for scar prevention completed