The PTH/PTHrP receptor can delay chondrocyte hypertrophy in vivo without activating phospholipase C.
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.
Guo
Jun
J
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Chung
Ung-Il
UI
Kondo
Hisatomo
H
Bringhurst
F Richard
FR
Kronenberg
Henry M
HM
D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006984:Hypertrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010281:Parathyroid Hormone / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D010703:Phorbol Esters / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D019379:Teriparatide / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000187:drug effects / Q000378:metabolism*
D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010703:Phorbol Esters; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D019379:Teriparatide; D005576:Colforsin; D000242:Cyclic AMP; D010738:Type C Phospholipases; C035748:parathyroid hormone (1-34)amide