title: Fibrillin-1 Regulates Skeletal Stem Cell Differentiation by Modulating TGFβ Activity Within the Marrow Niche.
abstract: A full understanding of the microenvironmental factors that control the activities of skeletal stem cells (also known as mesenchymal stem cells [MSCs]) in the adult bone marrow holds great promise for developing new therapeutic strategies to mitigate age-related diseases of bone and cartilage degeneration. Bone loss is an understudied manifestation of Marfan syndrome, a multisystem disease associated with mutations in the extracellular matrix protein and TGFβ modulator fibrillin-1. Here we demonstrate that progressive loss of cancellous bone in mice with limbs deficient for fibrillin-1 (Fbn1(Prx1-/-) mice) is accounted for by premature depletion of MSCs and osteoprogenitor cells combined with constitutively enhanced bone resorption. Longitudinal analyses of Fbn1(Prx1-/-) mice showed incremental bone loss and trabecular microarchitecture degeneration accompanied by a progressive decrease in the number and clonogenic potential of MSCs. Significant paucity of marrow fat cells in the long bones of Fbn1(Prx1-/-) mice, together with reduced adipogenic potential of marrow stromal cell cultures, indicated an additional defect in MSC differentiation. This postulate was corroborated by showing that an Fbn1-silenced osteoprogenitor cell line cultured in the presence of insulin yielded fewer than normal adipocytes and exhibited relatively lower PPARγ levels. Consonant with fibrillin-1 modulation of TGFβ bioavailability, cultures of marrow stromal cells from Fbn1(Prx1-/-) limb bones showed improper overactivation of latent TGFβ. In line with this finding, systemic TGFβ neutralization improved bone mass and trabecular microarchitecture along with normalizing the number of MSCs, osteoprogenitor cells, and marrow adipocytes. Collectively, our findings show that fibrillin-1 regulates MSC activity by modulating TGFβ bioavailability within the microenvironment of marrow niches.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Smaldone
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clayton
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: del Solar
authors.affiliation: Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Biomedical Research Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Pascual
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Wentworth
authors.affiliation: Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Biomedical Research Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.|Department of Biomedical Engineering, City College of New York, New York, NY, USA.
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Schaffler
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D055153:Stem Cell Niche / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: BONE MARROW NICHE; EXTRACELLULAR MATRIX; FIBRILLIN-1; MARFAN SYNDROME; OSTEOPENIA/OSTEOPOROSIS; TGFβ