The PTH/PTHrP receptor can delay chondrocyte hypertrophy in vivo without activating phospholipase C

Dev Cell. 2002 Aug;3(2):183-94. doi: 10.1016/s1534-5807(02)00218-6.

Abstract

One G protein-coupled receptor (GPCR) can activate more than one G protein, but the physiologic importance of such activation has not been demonstrated in vivo. We have generated mice expressing exclusively a mutant form of the PTH/PTHrP receptor (DSEL) that activates adenylyl cyclase normally but not phospholipase C (PLC). DSEL mutant mice exhibit abnormalities in embryonic endochondral bone development, including delayed ossification and increased chondrocyte proliferation. Analysis of the differentiation of embryonic metatarsals in vitro shows that PTH(1-34) and forskolin inhibit, whereas active phorbol ester stimulates, hypertrophic differentiation. Thus, PLC signaling via the PTH/PTHrP receptor normally slows the proliferation and hastens the differentiation of chondrocytes, actions that oppose the dominant effects of PTH/PTHrP receptors and that involve cAMP-dependent signaling pathways.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone and Bones / abnormalities*
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Division / genetics
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism*
  • Female
  • Hypertrophy / genetics*
  • Hypertrophy / metabolism
  • Hypertrophy / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Mutation / genetics
  • Parathyroid Hormone / pharmacology
  • Peptide Fragments / pharmacology
  • Phenotype
  • Phorbol Esters / pharmacology
  • RNA, Messenger / metabolism
  • Receptor, Parathyroid Hormone, Type 1
  • Receptors, Parathyroid Hormone / deficiency*
  • Receptors, Parathyroid Hormone / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Teriparatide / analogs & derivatives*
  • Teriparatide / pharmacology
  • Time Factors
  • Type C Phospholipases / drug effects
  • Type C Phospholipases / metabolism*

Substances

  • Parathyroid Hormone
  • Peptide Fragments
  • Phorbol Esters
  • RNA, Messenger
  • Receptor, Parathyroid Hormone, Type 1
  • Receptors, Parathyroid Hormone
  • Teriparatide
  • Colforsin
  • Cyclic AMP
  • Type C Phospholipases
  • parathyroid hormone (1-34)amide