The immunosuppressant FK506 promotes development of the chondrogenic phenotype in human synovial stromal cells via modulation of the Smad signaling pathway

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The immunosuppressant FK506 promotes development of the chondrogenic phenotype in human synovial stromal cells via modulation of the Smad signaling pathway K. Tateishi, M.D., C. Higuchi, M.D., Ph.D., W. Ando, M.D., K. Nakata, M.D., Ph.D., J. Hashimoto, M.D., Ph.D., D.A. Hart, M.D., Ph.D., H. Yoshikawa, M.D., Ph.D., N. Nakamura, M.D., Ph.D. Osteoarthritis and Cartilage Volume 15, Issue 6, Pages 709-718 (June 2007) DOI: 10.1016/j.joca.2007.01.006 Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Influence of FK506 on chondrogenic differentiation of hSSCs in vitro. Exposure to FK506 leads to significantly enlarged pellet culture size of SSCs (a). The sizes of pellets were quantified as CSA from 2-D images of pellets (b). FK506 enhancement of Alcian blue staining in the pellet cultures (c). Increases in the staining are prominent in the center area of FK506-treated pellet cultures and the staining intensity increased in a dose-dependent manner. Likewise, according to DMMB assays, FK506 exposure significantly increased GAG levels in the pellet cultures in a dose-dependent manner (d). (a) Bar=1mm. (c) Bar=100μm. Each error bar represents the standard error of the mean. Osteoarthritis and Cartilage 2007 15, 709-718DOI: (10.1016/j.joca.2007.01.006) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 FK506 enhances chondrogenic differentiation of SSCs and such enhancement is complementary to that induced by BMP2 and TGFβ1. In combination with BMP2 or TGFβ1, FK506 additively increased the size of pellet cultures and their staining properties to Alcian blue. In (a) on the upper left panel, the macroscopic appearance of a nontreated pellet culture is demonstrated within the square frame. The sizes of pellets were quantified as CSA (b), and GAG level of pellet cultures determined using the DMMB assay (d). The sizes and GAG levels of pellets were increased with FK506 treatment in a dose-dependent manner. RT-PCR showed that FK506-treated pellet cultures exhibited increased expression of collagen IIα1 and aggrecan irrespective of the presence of growth factors, and a significantly positive effect of FK506 was observed in combination with BMP2 or TGFβ1 (e). (a) Bar=1mm. (c) Bar=100μm. (e) Oblique line bar, TGFβ treatment group; open bar, BMP2 treatment group. Each error bar represents the standard error of the mean values. Osteoarthritis and Cartilage 2007 15, 709-718DOI: (10.1016/j.joca.2007.01.006) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 FK506 enhances chondrogenic differentiation of SSCs and such enhancement is complementary to that induced by BMP2 and TGFβ1. In combination with BMP2 or TGFβ1, FK506 additively increased the size of pellet cultures and their staining properties to Alcian blue. In (a) on the upper left panel, the macroscopic appearance of a nontreated pellet culture is demonstrated within the square frame. The sizes of pellets were quantified as CSA (b), and GAG level of pellet cultures determined using the DMMB assay (d). The sizes and GAG levels of pellets were increased with FK506 treatment in a dose-dependent manner. RT-PCR showed that FK506-treated pellet cultures exhibited increased expression of collagen IIα1 and aggrecan irrespective of the presence of growth factors, and a significantly positive effect of FK506 was observed in combination with BMP2 or TGFβ1 (e). (a) Bar=1mm. (c) Bar=100μm. (e) Oblique line bar, TGFβ treatment group; open bar, BMP2 treatment group. Each error bar represents the standard error of the mean values. Osteoarthritis and Cartilage 2007 15, 709-718DOI: (10.1016/j.joca.2007.01.006) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Influence of FK506 on phosphorylation of components of the Smad signaling pathways. The time course for induction of phospho-Smads in SSCs after FK506 stimulation as assessed by Western blotting. In FK506-treated cells, phospho-Smad1/5/8 and phospho-Smad3 levels were significantly higher than those in nontreated cells after 30min, 60min, and 120min (a,c). Significant differences between FK506-treated cells and nontreated cells were detected from the quantification of IOD measurements of phospho-Smad1/5/8 (3) to total-Smad1/5 (2/3) (b,d). The expression of phospho-Smad1/5/8 and phospho-Smad3 were significantly elevated in both the nuclear and cytoplasmic fractions after FK506 treatment (e). Each error bar represents the standard error of the mean. Osteoarthritis and Cartilage 2007 15, 709-718DOI: (10.1016/j.joca.2007.01.006) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Inhibition of Smad pathways partially abrogates FK506-induced chondrogenesis of hSSCs. In the presence of Noggin, a BMP antagonist, or SB431542, a TGFβ receptor I inhibitor, the FK506-mediated increases in size of pellet cultures were significantly decreased (a) and GAG levels also decreased with significant differences detected (b). FK506-mediated enhancement of chondrogenesis of hSSCs was partially suppressed by inhibition of Smad signaling pathways. The elevations in phospho-Smad1/5/8 levels after FK506 treatment were down-regulated by Noggin and those for phospho-Smad3 were down-regulated by SB431542 (c). Semiquantification revealed down-regulation by both inhibitors was significant (P<0.05) (d). Solid bar, FK506 treatment group; open bar, FK506 nontreatment group. Each error bar represents the standard error of the mean. Osteoarthritis and Cartilage 2007 15, 709-718DOI: (10.1016/j.joca.2007.01.006) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions