title: Substrate Modulus Regulates Osteogenic Differentiation of Rat Mesenchymal Stem Cells through Integrin β1 and BMP Receptor Type IA.
abstract: Osteoblast differentiation of mesenchymal stem cells is regulated by both soluble factor (e.g., bone morphogenetic proteins (BMP)) and mechanically transduced signaling, but the mechanisms have only been partially elucidated. In this study, physical association of BMP Receptor I (BMPRI) with integrin β1 sub-unit (Iβ1) was hypothesized to mediate osteoblast differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) on bone-like substrates. The effects of substrate modulus on osteoblast differentiation of MSCs were investigated for 2D poly(ester urethane) films with moduli varying from 5 - 266 MPa, which spans the range from collagen fibrils to trabecular bone. SMAD1/5 and p44/42 MAPK signaling, expression of markers of osteoblast differentiation, and matrix mineralization increased with increasing substrate modulus. The effects of substrate modulus on osteoblast differentiation were mediated by Iβ1, which was also expressed at higher levels on increasingly rigid substrates. Förster resonance energy transfer (FRET) and immunoprecipitation (IP) experiments showed that physical association of Iβ1 and BMP Receptor I (BMRPRI) increased with substrate modulus, resulting in activation of the BMP signaling pathway. Thus, these studies showed that integrin and BMP signaling converge to regulate osteoblast differentiation of MSCs, which may potentially guide the design of scaffolds and rhBMP-2 delivery systems for bone regeneration.
authors.affiliation: Department of Chemical and BIomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: R
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Chemical and BIomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Veterans Affairs: Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Merkel
authors.affiliation: Department of Veterans Affairs: Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Sterling
authors.affiliation: Department of Chemical and BIomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Guelcher