Membrane mediated signaling mechanisms are used differentially by metabolites of vitamin D3 in musculoskeletal cells

Barbara D. Boyan, Victor L. Sylvia, David D. Dean, Zvi Schwartz

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

1α,25(OH)2D3 and 24R,25(OH)2D3 mediate their effects on chondrocytes and osteoblasts in part through increased activity of protein kinase C (PKC). For both cell types, 1α,25(OH)2D3 exerts its effects primarily on more mature cells within the lineage, whereas 24R,25(OH)2D3 exerts its effects primarily on relatively immature cells. Studies using the rat costochondral cartilage growth plate as a model indicate that the two metabolites increase PKC activity by different mechanisms. In growth zone cells (prehypertrophic/upper hypertrophic cell zones), 1α,25(OH)2D3 causes a rapid increase in PKC that does not involve new gene expression. 1α,25(OH)2D3 binds its membrane receptor (1,25-mVDR), resulting in activation of phospholipase A2 and the rapid release of arachidonic acid, as well as activation of phosphatidylinositol-specific phospholipase C, resulting in formation of diacylglycerol and inositol-1,4,5-tris phosphate (IP3). IP3 leads to release of intracellular Ca2+ from the rough endoplasmic reticulum, and together with diacylglycerol, the increased Ca2+ activates PKC. PKC is then translocated to the plasma membrane, where it initiates a phosphorylation cascade, ultimately phosphorylating the extracellular signal-regulated kinase-1 and -2 (ERK1/2) family of MAP kinases (MAPK). PKC increases are maximal at 9 min, and MAPK increases are maximal at 90 min in these cells. By contrast, 24R,25(OH)2D3 increases PKC through activation of phospholipase D in resting zone cells. Peak production of diacylglycerol via phospholipase D2 is at 90 min, as are peak increases in PKC. Some of the effect is direct on existing plasma membrane PKC, but most is due to new PKC expression; translocation is not involved. Arachidonic acid and its metabolites also play differential roles in the mechanisms, stimulating PKC in growth zone cells and inhibiting PKC in resting zone cells. 24R,25(OH)2D3 decreases phospholipase A2 activity and prostaglandin production, thereby overcoming this potential inhibitory component, which may account for the delay in the PKC response. Ultimately, ERK1/2 is phosphorylated. PKC-dependent MAPK activity transduces some, but not all, of the physiological responses of each cell type to its respective vitamin D metabolite, suggesting that the membrane receptor(s) and nuclear receptor(s) may function interdependently to regulate proliferation and differentiation of musculoskeletal cells, but different pathways are involved at different stages of phenotypic maturation.

Original languageEnglish (US)
Pages (from-to)421-427
Number of pages7
JournalSteroids
Volume67
Issue number6
DOIs
StatePublished - 2002

Keywords

  • 1,25(OH)D
  • 24,25(OH)D
  • Chondrocytes
  • Membrane-associated steroid hormone receptors
  • Osteoblasts
  • Phospholipase A
  • Phospholipase C
  • Phospholipase D
  • Rapid responses to steroid hormones

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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