TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation.

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Nature medicine (Impact Factor: 27.14). 08/2009; 15(7):757-65. DOI: 10.1038/nm.1979
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteogenesis imperfecta (OI) is a heritable disorder, in both a dominant and recessive manner, of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms. Here, we show that excessive transforming growth factor-β (TGF-β) signaling is a mechanism of OI in both recessive (Crtap(-/-)) and dominant (Col1a2(tm1.1Mcbr)) OI mouse models. In the skeleton, we find higher expression of TGF-β target genes, higher ratio of phosphorylated Smad2 to total Smad2 protein and higher in vivo Smad2 reporter activity. Moreover, the type I collagen of Crtap(-/-) mice shows reduced binding to the small leucine-rich proteoglycan decorin, a known regulator of TGF-β activity. Anti-TGF-β treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI and improves the lung abnormalities in Crtap(-/-) mice. Hence, altered TGF-β matrix-cell signaling is a primary mechanism in the pathogenesis of OI and could be a promising target for the treatment of OI.
    Nature medicine 05/2014; · 27.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, as knowledge regarding the etiopathogenetic mechanisms of bone involvement characterizing many diseases has increased and diagnostic techniques evaluating bone health have progressively improved, the problem of low bone mass/quality in children and adolescents has attracted more and more attention, and the body evidence that there are groups of children who may be at risk of osteoporosis has grown. This interest is linked to an increased understanding that a higher peak bone mass (PBM) may be one of the most important determinants affecting the age of onset of osteoporosis in adulthood. This review provides an updated picture of bone pathophysiology and characteristics in children and adolescents with paediatric osteoporosis, taking into account the major causes of primary osteoporosis (PO) and evaluating the major aspects of bone densitometry in these patients. Finally, some options for the treatment of PO will be briefly discussed.
    Italian journal of pediatrics. 06/2014; 40(1):55.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The size and strength of bone is determined by two fundamental processes. One process, bone remodelling, renews the skeleton throughout life. In this process existing bone is resorbed by osteoclasts and replaced, in the same location, by osteoblasts. The other process is bone modelling, where bone formation and resorption occur at different sites so that the shape of bone is changed. Recent data suggests that both remodelling and modelling are controlled by signals between the cells that carry out these two processes. Osteoclasts both resorb bone, and provide inhibitory and stimulatory signals, including cardiotrophin-1 and sphingosine-1-kinase, to the osteoblast lineage thereby regulating their differentiation and activity on both trabecular and cortical surfaces. In addition, the osteoblast lineage, including osteoblast progenitors, matrix-producing osteoblasts, bone lining cells, and matrix-embedded osteocytes, produce both inhibitory and stimulatory factors that stimulate osteoclast differentiation. We will discuss the roles of osteoblast- and osteocyte-derived RANKL, and paracrine, autocrine and endocrine factors, such as ephrinB2, the IL-6 / gp130 family of cytokines, parathyroid hormone, and its related peptide, PTHrP. These factors not only stimulate RANKL production, but also stimulate osteoblast differentiation and activity. This review will focus on recent data, generated from pharmacological and genetic studies of mouse models and what these data reveal about these pathways at different stages of osteoblast differentiation and their impact on both bone remodelling and modelling in trabecular and cortical bone.
    Archives of Biochemistry and Biophysics 05/2014; · 3.37 Impact Factor

Full-text (2 Sources)

Available from
May 17, 2014