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Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone

Elena Kozhemyakina1, Todd Cohen, Tso-Pang Yao

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.

Molecular and Cellular Biology
|August 26, 2009
PubMed

Insights

Parathyroid hormone-related peptide (PTHrP) regulates chondrocyte maturation. PTHrP signaling, via protein phosphatase 2A (PP2A), controls histone deacetylase 4 (HDAC4) nuclear translocation, impacting collagen X expression and chondrocyte hypertrophy.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Chondrocyte maturation is a complex process crucial for skeletal development.
  • Parathyroid hormone-related peptide (PTHrP) signaling plays a key role in regulating chondrocyte differentiation.
  • Understanding the molecular mechanisms underlying PTHrP-mediated chondrogenesis is vital for addressing skeletal disorders.

Purpose of the Study:

  • To elucidate the molecular pathway by which PTHrP signaling regulates chondrocyte hypertrophy.
  • To investigate the role of histone deacetylase 4 (HDAC4) and protein phosphatase 2A (PP2A) in PTHrP-mediated gene expression.
  • To identify key regulatory steps in the repression of collagen X expression during chondrocyte maturation.

Main Methods:

  • Transfection of chondrocytes with collagen X-luciferase reporter constructs.
  • Administration of PTHrP or forskolin to modulate signaling pathways.
  • Analysis of MEF2 transcriptional activity and HDAC4 phosphorylation/localization.
  • Assessment of PP2A activity and its role in HDAC4 nuclear translocation using specific inhibitors and knockdown techniques.

Main Results:

  • PTHrP and forskolin inhibit collagen X reporter gene expression induced by Runx2, MEF2, and Smad1.
  • PTHrP/forskolin represses MEF2 transcriptional activity, which can be restored by forced MEF2 expression.
  • PTHrP/forskolin induces HDAC4 dephosphorylation (phospho-S246), promoting its nuclear translocation and MEF2 repression.
  • Forskolin activates an HDAC4 phosphatase, and PP2A is identified as critical for forskolin-induced HDAC4 nuclear translocation and collagen X repression.

Conclusions:

  • PTHrP signaling regulates chondrocyte hypertrophy through a pathway involving PP2A-mediated dephosphorylation and nuclear translocation of HDAC4.
  • HDAC4 nuclear translocation leads to the repression of MEF2 transcriptional activity, thereby inhibiting collagen X expression.
  • PP2A is a critical component of the PTHrP signaling cascade that controls chondrocyte maturation and collagen X expression.

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