Chondrocyte terminal differentiation, apoptosis, and type X collagen expression are downregulated by parathyroid hormone

Abstract

Parathyroid hormone (PTH) regulates calcium and phosphate homeostasis through the endocrine system. Parathyroid hormone-related peptide (PTHrP) is a heterogeneous polypeptide with sequence homology to PTH in its first 13 amino acid residues. Both bind and activate a common receptor, the type 1 PTH/PTHrP receptor (PTH1R). Activation of this Gprotein-coupled receptor by PTHrP has been shown to regulate chondrogenesis in a manner that attenuates chondrocyte hypertrophy. Here, we report the dose-response (10 Ϫ7 to 10 Ϫ15 M) effects of PTH on chondrogenesis using an avian sternal organ culture model. PTH increased cartilaginous tissue length and downregulated the deposition of type X collagen and its mRNA expression. In addition, PTH increased chondrocyte cell diameter in prehypertrophic and proliferative regions while decreasing chondrocyte apoptosis in the hypertrophic zone. In conclusion, these experiments demonstrate that PTH regulates cartilage growth, chondrocytic apoptosis, deposition of type X collagen protein, and expression of type X collagen mRNA. Type X collagen mRNA expression was downregulated by PTH in this organ culture model, but cell size, another marker for terminal differentiation, increased. © 2004 Wiley-Liss, Inc.Key words: hyaline cartilage; apoptosis; parathyroid hormone; parathyroid hormone-related peptide; chondrogenesis; parathyroid hormone receptor; type X collagen Parathyroid hormone (PTH) is one of the hormones and growth factors that regulate hyaline cartilage development. Classically, PTH is an 84-amino acid protein that regulates calcium and phosphate homeostasis primarily through actions on specific receptors in kidney and bone (Juppner et al., 1991;Juppner and Schipani, 1996;Bro and Olgaard, 1997). Native 1-84 PTH and 1-34 PTH fragments stimulate adenylate cyclase through a G-proteincoupled receptor (GPCR) with equal potency (Abou-Samra et al

In vitro regulation of proliferation and differentiation within a postnatal growth plate of the cranial base by parathyroid hormone‐related peptide (PTHrP)

“…This result agrees with observations of inhibited hypertrophy and/or mineralization in cultured embryonic mouse metatarsal rudiments when exposed to PTHrP Serra et al, 1999;Guo et al, 2002), and inhibited differentiation in cultured fetal chick sterna exposed to PTH (Harrington et al, 2004). In the present study the observed reduction in the amount of mineralization was significant after 1 day in culture, but it is likely that PTHrP begins acting immediately, as changes in gene expression are apparent within 4 h in embryonic metatarsi exposed to PTH (Guo et al, 2006).…”

PTH Stimulated Growth and Decreased Col‐X Deposition are Phosphotidylinositol‐3,4,5 Triphosphate Kinase and Mitogen Activating Protein Kinase Dependent in Avian Sterna

“…Indian hedgehog (Ihh) stimulates PTHrP production in the fetal periarticular growth plate and is synthesized by prehypertrophic chondrocytes (Lee et al, 1995;Kronenberg, 2006). In avian sterna, we have shown that PTHrP delayed differentiation, prolonged chondrocyte proliferation, and decreased cellular apoptosis (Harrington et al, 2004). Similar results were obtained with cultured growth plate chondrocytes; Col-X was decreased, proliferation increased and type II collagen was not changed (O'Keefe et al, 1997).…”

“…The sterna were incubated for 1.5-3 hr in 0.1% testicular hyaluronidase (280 U/mg; Sigma), and washed in phosphate buffered saline (PBS). Tissues were fixed and prepared as previously described (Hirsh et al, 1997;Harrington et al, 2004Harrington et al, , 2007. Monoclonal antibodies specific for Col-II, IX, or X [1:200; Developmental Studies Hybridoma Bank, Iowa City, IA; (Schmid and Linsenmayer, 1985)] were used.…”

Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells

“…Calcification is a pathological process that may lead to impairment of nutrient supply and disc metabolism in degenerative discs (Hristova et al, 2011). Although PTH is known to suppress type X collagen expression and calcification, while stimulating type II collagen (Harrington et al, 2004;Chang et al, 2009;Mwale et al, 2010), there has been no attempt to supplement PTH to cells of the degenerate human disc in order to inhibit ongoing mineral deposition and stimulate matrix repair. The present study, which investigated the effects of PTH on disc cells from degenerative discs, represented a first step towards the long-term goal of biological repair of the degenerative disc.…”