1α,25(OH)2D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60 activated matrix vesicle metalloproteinases

Barbara D. Boyan, Kevin L. Wong, Mimi Fang, Zvi Schwartz

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Growth plate chondrocytes produce proteoglycan-rich type II collagen extracellular matrix (ECM). During cell maturation and hypertrophy, ECM is reorganized via a process regulated by 1α,25(OH)2D3 and involving matrix metalloproteinases (MMPs), including MMP-3 and MMP-2. 1α,25(OH)2D3 regulates MMP incorporation into matrix vesicles (MVs), where they are stored until released. Like plasma membranes (PM), MVs contain the 1α,25(OH)2D3-binding protein ERp60, phospholipase A2 (PLA2), and caveolin-1, but appear to lack nuclear Vitamin D receptors (VDRs). Chondrocytes produce 1α,25(OH)2D3 (10-8 M), which binds ERp60, activating PLA2, and resulting lysophospholipids lead to MV membrane disorganization, releasing active MMPs. MV MMP-3 activates TGF-β1 stored in the ECM as large latent TGF-β1 complexes, consisting of latent TGF-β1 binding protein, latency associated peptide, and latent TGF-β1. Others have shown that MMP-2 specifically activates TGF-β2. TGF-β1 regulates 1α,25(OH)2D3-production, providing a mechanism for local control of growth factor activation. 1α,25(OH)2D3 activates PKCα in the PM via ERp60-signaling through PLA2, lysophospholipid production, and PLCβ. It also regulates distribution of phospholipids and PKC isoforms between MVs and PMs, enriching the MVs in PKCζ. Direct activation of MMP-3 in MVs requires ERp60. However, when MVs are treated with 1α,25(OH)2D3, PKCζ activity is decreased and PKCα is unaffected, suggesting a more complex feedback mechanism, potentially involving MV lipid signaling.

Original languageEnglish (US)
Pages (from-to)467-472
Number of pages6
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume103
Issue number3-5
DOIs
StatePublished - Mar 2007

Keywords

  • 1α,25(OH)D
  • Growth plate chondrocytes
  • Matrix metalloproteinases
  • Matrix vesicles
  • Rapid actions
  • TGF-β1 activation
  • TGF-β2

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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