Tamoxifen decreases fibroblast function and downregulates TGF(beta2) in dupuytren's affected palmar fascia.

BACKGROUND Dupuytren's contracture is a fibroproliferative disorder that is associated with increased collagen deposition. Isoforms of transforming growth factor beta (TGF(beta)), normally TGF(beta1) and TGF(beta2), are involved in the progressive fibrosis of Dupuytren's disease. It has been suggested that downregulation of TGF(beta) may be useful in the treatment of the condition. Tamoxifen, a synthetic nonsteroidal antiestrogen, is known to modulate the production of TGF(beta). This study examined the role of tamoxifen in decreasing fibroblast function and downregulating TGF(beta2). METHODS Primary cultures of fibroblasts were obtained from Dupuytren's affected fascia and carpal tunnel affected fascia as a control. Collagen lattices were prepared and populated with the fibroblasts. The fibroblast-populated collagen lattices (FPCL) were then measured for contraction every 24 h for 5 days. Supernatant was obtained from the culture medium following completion of the FPCL portion of the experiment and used for a TGF(beta2) immunoassay. RESULTS Dupuytren's affected fibroblasts contracted the FPCLs significantly more than carpal tunnel control fibroblasts. Treating the fibroblasts with tamoxifen caused a decreased contraction rate in both Dupuytren's affected fibroblasts and carpal tunnel controls. There was increased TGF(beta2) expression in the Dupuytren's affected fascia group compared to the carpal tunnel control group. Tamoxifen decreased TGF(beta2) expression in Dupuytren's affected fascia group but not in the carpal tunnel control group. CONCLUSION TGF(beta) appears to be the key cytokine in the fibrogenic nature of Dupuytren's disease. Tamoxifen treatment has been demonstrated to decrease the function of fibroblasts derived from Dupuytren's affected fascia and downregulated TGF(beta2) production in these same fibroblasts. These data suggest a method to manipulate and control Dupuytren's contracture in the clinical setting.

[1]  L. Hurst,et al.  The role of transforming growth factor beta in Dupuytren's disease. , 1996, The Journal of hand surgery.

[2]  L. L. Pu,et al.  Overexpression of Transforming Growth Factor Beta‐2 and Its Receptor in Rhinophyma: An Alternative Mechanism of Pathobiology , 2000, Annals of plastic surgery.

[3]  W. Border,et al.  Transforming growth factor beta in tissue fibrosis. , 1994, The New England journal of medicine.

[4]  L. Hurst,et al.  Platelet-derived growth factor in Dupuytren's disease. , 1992, The Journal of hand surgery.

[5]  G. Gabbiani,et al.  Dupuytren's contracture: fibroblast contraction? An ultrastructural study. , 1972, The American journal of pathology.

[6]  W. Border,et al.  Transforming Growth Factor β in Tissue Fibrosis , 1994 .

[7]  S. O'Kane,et al.  Transforming growth factor βs and wound healing , 1997 .

[8]  M. Gebhardt,et al.  Transforming growth factor-β: Possible roles in Dupuytren's contracture*† , 1995 .

[9]  A. Ghahary,et al.  Transforming growth factor-β in thermally injured patients with hypertrophic scars : Effects of interferon α-2b , 1998 .

[10]  M. J. Timmons.  Fibromatosis, desmoids, fibroblasts, and tamoxifen. , 1994, British journal of plastic surgery.

[11]  T. Tuan,et al.  Modulation of Collagen Synthesis by Transforming Growth Factor‐β in Keloid and Hypertrophic Scar Fibroblasts , 1994, Annals of plastic surgery.

[12]  D. Foreman,et al.  Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. , 1995, Journal of cell science.

[13]  L. Murphy.  Antiestrogen action and growth factor regulation , 2004, Breast Cancer Research and Treatment.

[14]  D. Foreman,et al.  Control of scarring in adult wounds by neutralising antibody to transforming growth factor β , 1992, The Lancet.

[15]  T. Tuan,et al.  Role of Growth Factors in Scar Contraction: An In Vitro Analysis , 1996, Annals of plastic surgery.

[16]  M. Sporn,et al.  Effects of transforming growth factor beta 1 on scar production in the injured central nervous system of the rat. , 1994, The European journal of neuroscience.

[17]  Renato V. Iozzo,et al.  Targeted Disruption of Decorin Leads to Abnormal Collagen Fibril Morphology and Skin Fragility , 1997, Journal of Cell Biology.

[18]  M. Ferguson,et al.  Fetal Wound Healing and the Development of Antiscarring Therapies for Adult Wound Healing , 1988 .

[19]  Gary R. Grotendorst,et al.  Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. , 1996, The Journal of investigative dermatology.

[20]  G. Magro,et al.  Myofibroblasts of Palmar Fibromatosis co‐express transforming growth factor‐alpha and epidermal growth factor receptor , 1997, The Journal of pathology.

[21]  D. Cox.  Transforming growth factor‐beta 3. , 1995, Cell biology international.

[22]  A. Ghahary,et al.  Fibroblasts from post-burn hypertrophic scar tissue synthesize less decorin than normal dermal fibroblasts. , 1998, Clinical science.

[23]  A. Isacchi,et al.  Basic fibroblast growth factor in Dupuytren's contracture. , 1992, The American journal of pathology.

[24]  W. Cance,et al.  Retroperitoneal fibrosis treated with tamoxifen. , 1995, The American surgeon.

[25]  R. Gelberman,et al.  Dupuytren's disease: Comparative growth dynamics and morphology between cultured myofibroblasts (nodule) and fibroblasts (cord) , 1984, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[26]  E. Ruoslahti,et al.  Transforming growth factor-beta in disease: the dark side of tissue repair. , 1992, The Journal of clinical investigation.

[27]  J. Preskitt,et al.  The response of retroperitoneal fibrosis to tamoxifen. , 1991, Surgery.

[28]  M. Robson,et al.  TGF-β2Activates Proliferative Scar Fibroblasts , 1999 .

[29]  Richard A.F. Clark,et al.  The Molecular and Cellular Biology of Wound Repair , 2012, Springer US.

[30]  J. Puzas,et al.  Comparative effects of growth factors on fibroblasts of Dupuytren's tissue and normal palmar fascia. , 1994, The Journal of hand surgery.

[31]  S. Ebbs,et al.  Desmoid tumours treated with triphenylethylenes. , 1992, European journal of cancer.

[32]  H. Kosmehl,et al.  TGFβ and bFGF synthesis and localization in Dupuytren's disease (nodular palmar fibromatosis) relative to cellular activity, myofibroblast phenotype and oncofetal variants of fibronectin , 1995, The Histochemical Journal.

[33]  L. L. Pu,et al.  Exogenous transforming growth factor beta(2) modulates collagen I and collagen III synthesis in proliferative scar xenografts in nude rats. , 1999, The Journal of surgical research.

[34]  E. Ruoslahti,et al.  Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. , 1994, The Biochemical journal.

[35]  G. Cherry,et al.  Topical tamoxifen--a potential therapeutic regime in treating excessive dermal scarring? , 1998, British journal of plastic surgery.

[36]  V. Jordan.  Growth factor regulation by tamoxifen is demonstrated in patients with breast cancer , 1993, Cancer.

[37]  G. Rayan,et al.  Generation of contractile force by cultured Dupuytren's disease and normal palmar fibroblasts. , 1994, Tissue & cell.

[38]  A. Colletta,et al.  Challenges: The pharmacological manipulation of members of the transforming growth factor beta family in the chemoprevention of breast cancer , 1993 .

[39]  M. Longaker,et al.  Expression of transforming growth factor beta 1, 2, and 3 proteins in keloids. , 1999, Annals of plastic surgery.

[40]  J. V. Vande Berg,et al.  The myofibroblast in Dupuytren's contracture. , 1991, Hand clinics.

[41]  M. Sporn,et al.  Effects of Transforming Growth Factor β1, on Scar Production in the Injured Central Nervous System of the Rat , 1994 .

[42]  A. Ghahary,et al.  Transforming growth factor-beta in thermally injured patients with hypertrophic scars: effects of interferon alpha-2b. , 1998, Plastic and reconstructive surgery.

[43]  C. Redmond,et al.  Effect of tamoxifen on serum insulinlike growth factor I levels in stage I breast cancer patients. , 1990, Journal of the National Cancer Institute.

[44]  D. Foreman,et al.  Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. , 1994, Journal of cell science.

[45]  P. Rouanet,et al.  Phase I Study of percutaneous 4-hydroxy-tamoxifen with analyses of 4-hydroxy-tamoxifen concentrations in breast cancer and normal breast tissue , 2004, Cancer Chemotherapy and Pharmacology.

[46]  M. Longaker,et al.  Tamoxifen Downregulates TGF-β Production in Keloid Fibroblasts , 1998 .