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TGF- and Chondrocytes TGF- Dependent Repression of MMP13 in - PowerPoint PPT Presentation

May 16, 2023 •30 likes •70 views

5/10/2013 TGF- and Chondrocytes TGF- Dependent Repression of MMP13 in Chondrocytes Well established role in chondrocyte Via a Smad3 and Runx2 Dependent differentiation, maturation, maintenance of resting state Pathway Aberrant

  1. 5/10/2013 TGF-β and Chondrocytes TGF-β Dependent Repression of MMP13 in Chondrocytes • Well established role in chondrocyte Via a Smad3 and Runx2 Dependent differentiation, maturation, maintenance of resting state Pathway • Aberrant TGF-β signaling associated with Osteoarthritis • Experimentally ? Dual Role on chondrocytes Daniel Thuillier, M.D. – ?Protective � Decreased MMP-13 Expression – ?Deleterious � Increased MMP-13 Expression TGF-β: Two Pathways � MMP-13 � MMP-13 1

  2. 5/10/2013 We Know… TGF-β inhibits terminal osteoblast differentiation via a Smad3 Chondrocyte Intrinsic Smad3 and Runx2 dependent pathway ColII-Cre;Smad3 fl/fl MIce • Can selectively knock out Smad3 in cells that are expressing Collagen II (i.e. Articular Cartilage Cells) • Allows for investigation of Chondrocyte Intrinsic role of Smad3 Therefore, we hypothesized that TGF- β inhibits Runx2-inducible MMP13 expression and terminal chondrocyte differentiation through Smad3-mediated repression of Runx2. Chrondrocyte-intrinsic Smad3 is required to maintain Molecular composition of growth plate and articular cartilage is disrupted in Col2-Cre;Smad3 fl/fl mice growth plate and articular cartilage Figure 1 A A E 1.4 Smad3 fl/fl Relative mRNA Expression C Smad3 fl/fl Col2-Cre;Smad3 fl/fl 1.4 Smad3 fl/fl Col2-Cre;Smad3 fl/fl Smad3 fl/fl Col2-Cre;Smad3 fl/fl 1.2 Relative mRNA Expression Col2-Cre;Smad3 fl/fl IgG 1.2 1.0 B 1.0 Smad3 fl/fl 0.8 0.8 mRNA Expression Relative Smad3 Col2-Cre;Smad3 fl/fl 1.5 0.6 0.6 0.4 0.4 0.2 1.0 0.2 0.0 0.0 MMP-13 Col2 * Agn 0.5 B F Smad3 fl/fl Col2-Cre;Smad3 fl/fl 0.0 D P14 P60 P90 E Smad3 fl/fl Smad3 fl/fl articular cartilage Col2-Cre;Smad3 fl/fl VDIPEN Agn C G Col2-Cre; Smad3 fl/fl F 8 * … 6 Modified Smad3 fl/fl 4 Col2 growth plate GPQG 2 D H 0 Col2-Cre; Smad3 fl/fl IgG Pre-immune 2

  3. 5/10/2013 TGF- β exposure in cultured primary chondrocytes and ATDC5 TGF-β: Two Pathways cells show both repression and induction of MMP-13 expression in a time-dependent manner � MMP-13 � MMP-13 TGF- β mediated repression of MMP-13 is dependent upon TGF- β mediated repression and induction of MMP-13 is Smad3 in both ATDC5s and primary chondrocytes dependent upon Runx2 ATDC5 ColII-Cre; Smad3 fl/fl 3

  4. 5/10/2013 Thank You • Tamara Alliston Summary • Carol Chen • TGF-β – Dual Role in Chondrocytes both • Emily Chin protective and deleterious – Can Repress MMP-13 via Smad3 and Runx2 4

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