TGF-β1-induced Migration of Bone Mesenchymal Stem Cells Couples Bone Resorption and Formation

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Nature medicine (Impact Factor: 27.36). 08/2009; 15(7):757-65. DOI: 10.1038/nm.1979
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Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-beta1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-beta1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-beta1 in the bone marrow. Treatment with a TGF-beta type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-beta1 functions to couple bone resorption and formation, modulation of TGF-beta1 activity could be an effective treatment for bone remodeling diseases.

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    • "The TEL anti-proliferative activity and induction of beige fat phenotype in mesenchymal cells are mediated through PPARγ, as well as TEL activity to antagonize the negative effect of ROSI on both osteoblast phenotype and TGFβ/BMP signaling pathway. The TGFβ/BMP signaling is essential for regulation of bone acquisition and bone remodeling, mainly through the regulation of marrow MSC lineage commitment and osteoblast maturation [47], and its activity is compromised with aging [48], in osteoporotic patients [49], and in patients on TZD therapy [50]. All these conditions are associated with increased lipogenic, pro-adipocytic activity of PPARγ in marrow cells of mesenchymal lineage. "
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    ABSTRACT: Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced "browning" of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat "browning" activity and a lack of anti-osteoblastic activity.
    PLoS ONE 05/2014; 9(5):e96323. DOI:10.1371/journal.pone.0096323 · 3.23 Impact Factor
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    • "Even though the effects of TGF-β or PDGF alone on the osteogenic differentiation of undifferentiated mesenchymal cells have been reported in detail (17,40,42), their combined effects still remain unknown to date. In this study, we investigated the osteogenic differentiation of human MSCs (hMSCs) following stimulation with exogenous TGF-β and PDGF. "
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    ABSTRACT: Transforming growth factor-β (TGF-β) is a critical regulator of osteogenic differentiation and the platelet-derived growth factor (PDGF) is a chemoattractant or mitogen of osteogenic mesenchymal cells. However, the combined effects of these regulators on the osteogenic differentiation of mesenchymal cells remains unknown. In this study, we investigated the effects of TGF-β and/or PDGF on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). The TGF-β-induced osteogenic differentiation of UE7T-13 cells, a bone marrow-derived hMSC line, was markedly enhanced by PDGF, although PDGF alone did not induce differentiation. TGF-β induced extracellular signal-regulated kinase (ERK) phosphorylation and PDGF induced Akt phosphorylation. In addition, the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor, U0126, suppressed the osteogenic differentiation induced by TGF-β alone. Moreover, U0126 completely suppressed the osteogenic differentiation synergistically induced by TGF-β and PDGF, whereas the phosphoinositide-3-kinase (PI3K) inhibitor, LY294002, only partially suppressed this effect. These results suggest that the enhancement of TGF-β-induced osteogenic differentiation by PDGF-induced PI3K/Akt-mediated signaling depends on TGF-β-induced MEK activity. Thus, PDGF positively modulates the TGF-β-induced osteogenic differentiation of hMSCs through synergistic crosstalk between MEK- and PI3K/Akt-mediated signaling.
    International Journal of Molecular Medicine 03/2014; 33(3):534. DOI:10.3892/ijmm.2013.1606 · 2.09 Impact Factor
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    • "There is also much interest in the possibility that PTH treatment results in transient activation of osteoclasts, that in turn produce activity that enhances the osteoblast differentiation effect. The latter may be independent of resorption,[45,46] or may result from the release of growth factors (transforming growth factor beta [TGFβ], insulin-like growth factor-1 [IGF-1]) in the resorption process[47,48] that enhance the availability of mesenchymal stem cells (TGFβ), or their differentiation in the osteoblast lineage (IGF-1). These aspects of the anabolic action of PTH are summarised in Figure 2. "
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    ABSTRACT: Bone is continuously remodelled at many sites asynchronously throughout the skeleton, with bone formation and resorption balanced at these sites to retain bone structure. Negative balance resulting in bone loss and osteoporosis, with consequent fractures, has mainly been prevented or treated by anti-resorptive drugs that inhibit osteoclast formation and/or activity, with new prospects now of anabolic treatments that restore bone that has been lost. The anabolic effectiveness of parathyroid hormone has been established, and an exciting new prospect is presented of neutralising antibody against the osteocyte protein, sclerostin. The cellular actions of these two anabolic treatments differ, and the mechanisms will need to be kept in mind in devising their best use. On present evidence it seems likely that treatment with either of these anabolic agents will need to be followed by anti-resorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for safe, effective anti-resorptive drugs.
    02/2014; 21(1):8-20. DOI:10.11005/jbm.2014.21.1.8
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