24,25-(OH)2D3 regulates cartilage and bone via autocrine and endocrine mechanisms

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

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

The purpose of this paper is to summarize recent advances in our understanding of the physiological role of 24(R),25(OH)2D3 in bone and cartilage and its mechanism of action. With the identification of a target cell, the growth plate resting zone (RC) chondrocyte, we have been able to use cell biology methodology to investigate specific functions of 24(R),25(OH)2D3 and to determine how 24(R),25(OH)2D3 elicits its effects. These studies indicate that there are specific membrane-associated signal transduction pathways that mediate both rapid, nongenomic and genomic responses of RC cells to 24(R),25(OH)2D3. 24(R),25(OH)2D3 binds RC chondrocyte membranes with high specificity, resulting in an increase in protein kinase C (PKC) activity. The effect is stereospecific; 24R,25(OH)2D3, but not 24S,25-(OH)2D3, causes the increase, indicating a receptor-mediated response. Phospholipase D-2 (PLD2) activity is increased, resulting in increased production of diacylglycerol (DAG), which in turn activates PKC. 24(R),25(OH)2D3 does not cause translocation of PKC to the plasma membrane, but activates existing PKCα. There is a rapid decrease in Ca2+ efflux, and influx is stimulated. 24(R),25(OH)2D3 also reduces arachidonic acid release by decreasing phospholipase A2 (PLA2) activity, thereby decreasing available substrate for prostaglandin production via the action of cyclooxygenase-1. PGE2 that is produced acts on the EP1 and EP2 receptors expressed by RC cells to downregulate PKC via protein kinase A, but the reduction in PGE2 decreases this negative feedback mechanism. Both pathways converge on MAP kinase, leading to new gene expression. One consequence of this is production of new matrix vesicles containing PKCα and PKCζ and an increase in PKC activity. The chondrocytes also produce 24(R),25(OH)2D3, and the secreted metabolite acts directly on the matrix vesicle membrane. Only PKCζ is directly affected by 24(R),25(OH)2D3 in the matrix vesicles, and activity of this isoform is inhibited. This effect may be involved in the control of matrix maturation and turnover. 24(R),25(OH)2D3 causes RC cells to mature along the endochondral developmental pathway, where they become responsive to 1α,25(OH)2D3 and lose responsiveness to 24(R),25(OH)2D3, a characteristic of more mature growth zone (GC) chondrocytes. 1α,25(OH)2D3 elicits its effects on GC through different signal transduction pathways than those used by 24(R),25(OH)2D3. These studies indicate that 24(R),25(OH)2D3 plays an important role in endochondral ossification by regulating less mature chondrocytes and promoting their maturation in the endochondral lineage.

Original languageEnglish (US)
Pages (from-to)363-374
Number of pages12
JournalSteroids
Volume66
Issue number3-5
DOIs
Publication statusPublished - May 1 2001

    Fingerprint

Keywords

  • 1α,25(OH)D
  • 24(R),25(OH)D
  • Chondrocytes
  • Growth plate
  • Rapid actions
  • Vitamin D
  • Vitamin D receptors

ASJC Scopus subject areas

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

Cite this