Solving The Dupuytren Puzzle

Notes on theories of the origin of Dupuytren disease.

Any theory of the core biology of Dupuytren disease has to explain these factors:

• Familial influence
• Age influence
• Gender Influence
• Relationship to mechanical forces
• Transformation of adjacent tissues
• Myofibroblast persistence
• Variability
• Appearance only at certain locations
• Quiescence

Starting Points: The matrix is abnormal. The cells are abnormal. Which comes first?

Abnormal Matrix

• Stiffness, from…
  • Diabetic glycosylation (REFS)
  • Protein folding
  • Lysyl Oxidase overexpression (Van Der Slot 2004)
  • MMP inhibition (Hutchinson 1998)
• Cytokine conditioning

Abnormal local cells

• Hypersensitive Fibroblast
  • Relaxin receptor (Bennett 2010)
    • Downregulated by androgens (Dehghan 2014)
    • Upregulated by estrogen (19416165)
  • Angiotensin II issue (Chow 2014)
• Lingering Myofibroblasts

Unexplained biologic comorbidities – what explains these?

• Hypothyroidism (Macaulay 2012, Cakir 2003)
• Hyperlipidemia (Macaulay 2012)
• Diabetes Mellitus (Macaulay 2012)
• Early Mortality (Wilbrand 2005, Mikkelsen 1999, Gudmundsson 2002)
• Cancer risk (Macaulay 2012, Gudmundsson 2002)
• Cardiovascular disease (Wilbrand 2005)
• Epilepsy Seizures after closed head trauma are due to intracranial scar contracture – could Dupuytren patients be more prone to this? TGF beta blockade prevents experimental post traumatic seizures (REF). TGF beta is essential to albumin induced seizure model (Cacheaux 2009)

Unexplained lifestyle comorbidities – are these real? What is their role?

• Antidepressant use (Macaulay 2012)
• Alcoholism (REFS)
• Smoking (REFS)
• Seizure Meds (REFS)
• Vibration exposure (REFS)
• Strenuous hand use (REFS)

Dupuytren Literature