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Thrombospondin-1 inhibits osteogenic differentiation of human mesenchymal stem cells through latent TGF-? activation.

ABSTRACT: Transforming growth factor-? (TGF-?) is a critical regulator of bone development and remodeling. TGF-? must be activated from its latent form in order to signal. Thrombospondin-1 (TSP1) is a major regulator of latent TGF-? activation and TSP1 control of TGF-? activation is critical for regulation of TGF-? activity in multiple diseases. Bone marrow-derived mesenchymal stem cells (MSCs) have osteogenic potential and they participate in bone remodeling in injury and in response to tumor metastasis. Since both TSP1 and TGF-? inhibit osteoblast differentiation, we asked whether TSP1 blocks osteoblast differentiation of MSCs through its ability to stimulate TGF-? activation. TSP1 added to human bone marrow-derived MSCs under growth conditions increases active TGF-?. Cultured MSCs express TSP1 and both TSP1 expression and TGF-? activity decrease during osteoblast differentiation. TSP1 and active TGF-? block osteoblast differentiation of MSCs grown in osteogenic media as measured by decreased Runx2 and alkaline phosphatase expression. The inhibitory effect of TSP1 on osteoblast differentiation is due to its ability to activate latent TGF-?, since a peptide which blocks TSP1 TGF-? activation reduced TGF-? activity and restored osteoblast differentiation as measured by increased Runx2 and alkaline phosphatase expression. Anti-TGF-? neutralizing antibody also increased alkaline phosphatase expression in the presence of TSP1. These studies show that TSP1 regulated TGF-? activity is a critical determinant of osteoblast differentiation.

SUBMITTER: Bailey Dubose K

PROVIDER: S-EPMC3372697 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Thrombospondin-1 inhibits osteogenic differentiation of human mesenchymal stem cells through latent TGF-β activation.

Bailey Dubose Kimberly K Zayzafoon Majd M Murphy-Ullrich Joanne E JE

Biochemical and biophysical research communications 20120511 3

Transforming growth factor-β (TGF-β) is a critical regulator of bone development and remodeling. TGF-β must be activated from its latent form in order to signal. Thrombospondin-1 (TSP1) is a major regulator of latent TGF-β activation and TSP1 control of TGF-β activation is critical for regulation of TGF-β activity in multiple diseases. Bone marrow-derived mesenchymal stem cells (MSCs) have osteogenic potential and they participate in bone remodeling in injury and in response to tumor metastasis. ...[more]

PMID: 22583901

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Project description:BackgroundPanax Notoginseng is a well-known Chinese medicinal herb which has been used in China for treatment of bone fracture for hundreds of years. However, the specific biological mechanisms of osteogenic effect of PNS are not well understood.MethodsIn this study, newborn rabbit BMSCs were isolated, and then identified by the positive expression rates of cell surface markers, including CD29, CD45 and HLA-DR, which were detected by flow cytometry(FCM). After the lentivirus-induced cell model of TGF-β1 gene silencing was established, the interference efficiency was tested by q-PCR and Western blot, and the growth curve of silencing cells was drawn by MTT so as to grasp the growth rhythm of silencing cells. In the alizarin red-staining experiment, the effect of 100 mg/L PNS on the activity of intracellular ALP of TGF-β1 gene silencing BMSCs was detected, so as to observe the effect of 100 mg/L PNS on the formation of calcium nodes of gene silencing BMSCs.ResultsBy separating rabbit BMSCs, the lentivirus-induced cell model of TGF-β1 gene silencing was established. Both TGF-β1 mRNA and protein expression were restrained significantly, and the target gene kept silence stably via the verification of q-PCR and Western blot; there was no significant differences of the growth curve between RNAi cells and normal cells; the activity of intracellular APL in 100 mg RNAi group was obviously lower than that in 100 mg group (p < 0.05), but higher than that in the normal group; in the alizarin red-staining experiment, it focused on the effects of PNS on the formation of calcium nodes of gene silencing BMSCs, which showed that calcium nodes could be formed in 100 mg RNAi group but its quantity was lower than that of 100 mg group (p < 0.05).ConclusionsIt was shown that silencing TGF-β1 gene could interrupt the osteogenic effects of PNS. PNS may have a promoting effect on osteogenic differentiation of rabbits' BMSCs in vitro by up-regulating the gene expression of TGF-β1.

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Thrombospondin-1 inhibits osteogenic differentiation of human mesenchymal stem cells through latent TGF-? activation.

Publications

Thrombospondin-1 inhibits osteogenic differentiation of human mesenchymal stem cells through latent TGF-β activation.

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