PTH/PTHrP receptor delays chondrocyte hypertrophy via both Runx2-dependent and -independent pathways.
The transcription factor, Runx2, promotes chondrocyte hypertrophy, whereas parathyroid hormone-related protein (PTHrP) delays this process. To examine whether PTHrP suppresses chondrocyte hypertrophy via Runx2-dependent or -independent pathways, Runx2 expression and chondrocyte differentiation were analyzed using bones from embryonic limbs of wild type and Runx2(-/-) mice. Treatment of cultured rudiments with PTH dramatically suppresses Runx2 mRNA levels in hypertrophic chondrocytes. PTH-induced delay of chondrocyte hypertrophy was observed in cultured tibiae from both Runx2(-/-) and wild-type embryos. This delay was also seen after PTH administration to limbs from wild type and Runx2(-/-) mice expressing Runx2 in chondrocytes via a collagen 2 promoter-driven transgene. To further explore Runx2-dependent and -independent effects of PTHrP, we examined embryonic tibiae and femurs from littermates null for PTHrP, Runx2, or both genes. Runx2(-/-) femurs exhibited no vascular invasion or chondrocytes expressing collagen type X or osteopontin mRNA. In contrast, Runx2(-/-)/PTHrP(-/-) mice exhibited limited vascular invasion and some chondrocytes expressing collagen X or osteopontin mRNA. In both tibia and femur, Runx2(-/-)/PTHrP(-/-) mice exhibited expanded regions of proliferating chondrocytes when compared to the same regions in PTHrP(-/-) mice. These data indicate that the delayed hypertrophy induced by PTHrP is mediated by both Runx2-dependent and -independent mechanisms.
Guo
Jun
J
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Chung
Ung-Il
UI
Yang
Dehong
D
Karsenty
Gerard
G
Bringhurst
F Richard
FR
Kronenberg
Henry M
HM
D000818:Animals; D049108:Cell Enlargement; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005269:Femur / Q000196:embryology / Q000473:pathology; D006984:Hypertrophy; D008682:Metatarsal Bones / Q000196:embryology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010281:Parathyroid Hormone / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D050659:Core Binding Factor Alpha 1 Subunit; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; C493716:Runx2 protein, mouse