Myocilin stimulates osteogenic differentiation of mesenchymal stem cells through mitogen-activated protein kinase signaling

J Biol Chem. 2013 Jun 7;288(23):16882-16894. doi: 10.1074/jbc.M112.422972. Epub 2013 Apr 29.

Abstract

Myocilin is a secreted glycoprotein that is expressed in ocular and non-ocular tissues. Mutations in the MYOCILIN gene may lead to juvenile- and adult-onset primary open-angle glaucoma. Here we report that myocilin is expressed in bone marrow-derived mesenchymal stem cells (MSCs) and plays a role in their differentiation into osteoblasts in vitro and in osteogenesis in vivo. Expression of myocilin was detected in MSCs derived from mouse, rat, and human bone marrow, with human MSCs exhibiting the highest level of myocilin expression. Expression of myocilin rose during the course of human MSC differentiation into osteoblasts but not into adipocytes, and treatment with exogenous myocilin further enhanced osteogenesis. MSCs derived from Myoc-null mice had a reduced ability to differentiate into the osteoblastic lineage, which was partially rescued by exogenous extracellular myocilin treatment. Myocilin also stimulated osteogenic differentiation of wild-type MSCs, which was associated with activation of the p38, Erk1/2, and JNK MAP kinase signaling pathways as well as up-regulated expression of the osteogenic transcription factors Runx2 and Dlx5. Finally, cortical bone thickness and trabecular volume, as well as the expression level of osteopontin, a known factor of bone remodeling and osteoblast differentiation, were reduced dramatically in the femurs of Myoc-null mice compared with wild-type mice. These data suggest that myocilin should be considered as a target for improving the bone regenerative potential of MSCs and may identify a new role for myocilin in bone formation and/or maintenance in vivo.

Keywords: Differentiation; Glycoprotein Secretion; MAP Kinases (MAPKs); Mesenchymal Stem Cells; Myocilin; Osteogenesis; Signaling.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Core Binding Factor Alpha 1 Subunit / biosynthesis
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Osteoblasts / cytology
  • Osteoblasts / metabolism*
  • Osteogenesis / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Up-Regulation / physiology

Substances

  • Core Binding Factor Alpha 1 Subunit
  • Cytoskeletal Proteins
  • DLX5 protein, human
  • Distal-less homeobox proteins
  • Dlx5 protein, mouse
  • Eye Proteins
  • Glycoproteins
  • Homeodomain Proteins
  • RUNX2 protein, human
  • Runx2 protein, mouse
  • Runx2 protein, rat
  • Transcription Factors
  • trabecular meshwork-induced glucocorticoid response protein
  • Extracellular Signal-Regulated MAP Kinases