The cyclin-dependent kinase inhibitor p57(Kip2) mediates proliferative actions of PTHrP in chondrocytes.
Parathyroid hormone-related peptide (PTHrP) is a positive regulator of chondrocyte proliferation during bone development. In embryonic mice lacking PTHrP, chondrocytes stop proliferating prematurely, with accelerated differentiation. Because the bone phenotype of mice lacking the cyclin-dependent kinase inhibitor p57(Kip2) is the opposite of the PTHrP-null phenotype, we hypothesized that PTHrP's proliferative actions in chondrocytes might be mediated by opposing p57. We generated p57/PTHrP-null embryos, which showed partial rescue of the PTHrP-null phenotype. There was reversal of the loss of proliferative chondrocytes in most bones, with reversal of the accelerated differentiation that occurs in the PTHrP-null phenotype. p57 mRNA and protein were upregulated in proliferative chondrocytes in the absence of PTHrP. Metatarsal culture studies confirmed the action of PTHrP to decrease p57 mRNA and protein levels in a model in which parathyroid hormone (PTH), used as an analog of PTHrP, increased chondrocyte proliferation rate and the length of the proliferative domain. PTH treatment of p57-null metatarsals had no effect on proliferation rate in round proliferative chondrocytes but still stimulated proliferation in columnar chondrocytes. These studies suggest that the effects of PTHrP on both the rate and extent of chondrocyte proliferation are mediated, at least in part, through suppression of p57 expression.
MacLean
Helen E
HE
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Guo
Jun
J
Knight
Melissa C
MC
Zhang
Pumin
P
Cobrinik
David
D
Kronenberg
Henry M
HM
D000818:Animals; D001846:Bone Development / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects*; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects*; D024121:Collagen Type X / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008682:Metatarsal Bones / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D009924:Organ Culture Techniques; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D014457:Ulna / Q000196:embryology
C493965:Cdkn1c protein, mouse; D024121:Collagen Type X; D050761:Cyclin-Dependent Kinase Inhibitor p57; D009687:Nuclear Proteins; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1