PTH/PTHrP receptor delays chondrocyte hypertrophy via both Runx2-dependent and -independent pathways

Abstract

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.

The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification

“…This effect of IHH is mediated by Gli2, and Gli2-dependent stimulation of secretion of parathyroid hormone-related peptide (PTHrP; Vortkamp et al 1996, Kronenberg 2006, Joeng & Long 2009). PTHrP suppresses hypertrophy, thus keeping the cells in a proliferative state (Lee et al 1996).…”

“…PTHrP suppresses hypertrophy, thus keeping the cells in a proliferative state (Lee et al 1996). PTHrP exerts this effect at least in part through inhibition of expression of the transcription factor RUNX2; RUNX2 induces chondrocytic transcription of hypertrophy-associated genes including col10a1 and promotes hypertrophy (Lefebvre & Smits 2005, Guo et al 2006. The suppression of hypertrophy by PTHrP is probably also mediated by SOX9, which is activated by PTHrP through protein kinase A-dependent phosphorylation and indirectly inhibits RUNX2 expression (Huang et al 2000, Akiyama et al 2002, Yamashita et al 2009).…”

Cell polarity

“…IHH signaling promotes two antagonistic processes in chondrocytes, proliferation and hypertrophy (the terminal phase of chondrocyte differentiation). [34][35][36] IHH signaling also promotes PTHrP expression, which, in turn, maintains the pool of resting chondrocytes and limits hypertrophy. 31,34,37 The output of this central PTHrP/IHH feedback loop is modified by the actions of other graded and regional secreted signaling molecules, such as FGFs, Wnts and transforming growth factorβ/bone morphogenetic protein superfamily factors (TGFβ/BMPs).…”

Effect of parathyroid hormone-related protein in an in vitro hypertrophy model for mesenchymal stem cell chondrogenesis

“…Parathyroid hormone-related protein (PTHrP) controls chondrocyte maturation during endochondral bone development [11,12]. It is expressed in perichondrial cells and peri-articular chondrocytes, binds to its receptor on proliferating and pre-hypertrophic chondrocytes and slows down maturation.…”