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Transforming Growth Factor β3 Regulates the Versican Variants in the Extracellular Matrix-Rich Uterine Leiomyomas

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, Reproductive Biology and Medicine Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

Minnie Malik, PhD

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Candace Y. Parker, MD

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, Reproductive Biology and Medicine Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

Doina Joseph, MS

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Phyllis C. Leppert, MD, PhD

Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina

James H. Segars, MD

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, Reproductive Biology and Medicine Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

William H. Catherino, MD, PhD

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, wcatherino{at}usuhs.mil, Reproductive Biology and Medicine Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

Uterine leiomyoma are common, benign tumors that are enriched in extracellular matrix. The tumors are characterized by a disoriented and loosely packed collagen fibril structure similar to other diseases with disrupted Transforming growth factor β (TGF-β) signaling. Here we characterized TGF-β3 signaling and the expression patterns of the critical extracellular matrix component versican in leiomyoma and myometrial tissue and cell culture. We also demonstrate the regulation of the versican variants by TGF-β3. Using leiomyoma and matched myometrium from 15 patients, messenger RNA (mRNA) from leiomyoma and myometrium was analyzed by semiquantitative real time reverse transcription—polymerase chain reaction (RT-PCR), while protein analysis was done by western blot. Transforming growth factor β3 transcripts were increased 4-fold in leiomyoma versus matched myometrium. Phosphorylated-TGF-β RII and phosphorylated-Smad 2/3 complex were greater in leiomyoma as documented by Western blot. The inhibitor Smad7 transcripts were decreased 0.44-fold. The glycosaminoglycan (GAG)-rich versican variants were elevated in leiomyoma versus myometrial tissue: specifically V0 (4.27 ± 1.12) and V1 (2.01 ± 0.27). Treatment of leiomyoma and myometrial cells with TGF-β3 increased GAG-rich versican variant expression 7 to 12 fold. Neutralizing TGF-β3 antibody decreased the expression of the GAG-rich versican variants 2 to 8 fold in leiomyoma cells. Taken together, the aberrant production of excessive and disorganized extracellular matrix that defines the leiomyoma phenotype involves the activation of the TGF-β signaling pathway and excessive production of GAG-rich versican variants.

Key Words: Versican variants • TGF-β3 • leiomyomas • immortalized cells • extracellular matrix.

This version was published on December 1, 2009

Reproductive Sciences, Vol. 16, No. 12, 1153-1164 (2009)
DOI: 10.1177/1933719109343310


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