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
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone and Bones / abnormalities*
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Bone and Bones / metabolism
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Bone and Bones / pathology
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Cell Differentiation / drug effects
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Cell Differentiation / genetics*
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Cell Division / genetics
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Chondrocytes / metabolism*
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Chondrocytes / pathology
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Colforsin / pharmacology
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Cyclic AMP / metabolism*
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Female
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Hypertrophy / genetics*
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Hypertrophy / metabolism
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Hypertrophy / pathology
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Male
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Mice
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Mice, Knockout
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Mutation / genetics
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Parathyroid Hormone / pharmacology
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Peptide Fragments / pharmacology
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Phenotype
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Phorbol Esters / pharmacology
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RNA, Messenger / metabolism
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Receptor, Parathyroid Hormone, Type 1
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Receptors, Parathyroid Hormone / deficiency*
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Receptors, Parathyroid Hormone / genetics
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Signal Transduction / drug effects
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Signal Transduction / genetics*
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Teriparatide / analogs & derivatives*
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Teriparatide / pharmacology
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Time Factors
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Type C Phospholipases / drug effects
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Type C Phospholipases / metabolism*
Substances
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Parathyroid Hormone
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Peptide Fragments
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Phorbol Esters
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RNA, Messenger
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Receptor, Parathyroid Hormone, Type 1
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Receptors, Parathyroid Hormone
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Teriparatide
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Colforsin
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Cyclic AMP
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Type C Phospholipases
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parathyroid hormone (1-34)amide