Disease relevance of PTHLH

• Furthermore, infection with a Smad 3-expressing retrovirus mimicked the effects of exogenously added TGF-beta, and induced PTHrP mRNA expression in the infected chondrocyte culture [1].
• PTH-related peptide (PTHrP) has been shown to be responsible for the hormonal hypercalcemia of malignancy [2].
• PTH/PTHrP receptor gene expression was evaluated in situ in avian epiphyseal growth plates taken from normal, rachitic and tibial dyschondroplasia (TD) afflicted chicks induced by thiram or by genetic selection [3].
• Activation of this G-protein-coupled receptor by PTHrP has been shown to regulate chondrogenesis in a manner that attenuates chondrocyte hypertrophy [4].

High impact information on PTHLH

• A synthetic hybrid peptide was synthesized, [Ala29]PTH(28-48), in which alanine replaced glutamine at position 29, as in the PTH-rP molecule [5].
• Parathyroid hormone (PTH) receptor bindings were examined in the membrane fraction of the calvaria and the kidney of the hen by the use of [125I]PTH-related protein (PTHrP) binding assays [6].
• These findings underscore the importance of cellular Ca(2+) in GPC function and suggest that PTHrP action in the growth plate is at least partially regulated by changes in basal [Ca(2+)](i) [7].
• Since EGTA mimicked the effect of parathyroid hormone-related peptide (PTHrP) on GPC maturation, we examined the effect of low [Ca(2+)](i) on PTHrP expression [7].
• PTHrP expression was examined in chondrocytes isolated from 3- to 5-week-old chick long bones [8].

Biological context of PTHLH

• PTHrP regulates the rate of chondrocyte differentiation during endochondral bone formation [1].
• Chondrocyte differentiation during embryonic bone growth is controlled by interactions between PTHrP and Indian hedgehog [9].
• These results suggest that alterations in the PTH/PTHrP receptor gene expression are associated with rickets but not with TD [3].
• Regulation of phenotype in chick tibial growth plate chondrocytes (GPCs) by parathyroid hormone-related peptide (PTHrP) is facilitated via signaling through three pathways: protein kinase A (PKA), protein kinase C (PKC) and inositol-1,4,5-trisphosphate-induced Ca2+ transients [10].
• It is possible that PTH or PTHrP, or both, act as a systemic, developmental modulator of cellular proliferation and differentiation in the growth plate [11].

Anatomical context of PTHLH

• Furthermore, while cells from the epiphysis are considered the physiologic source of PTHrP, the relative expression of PTHrP in epiphyseal and growth plate chondrocytes has not been defined [8].
• In the oviduct tissues of adult birds, PTHrP mRNA was detected in the isthmus (membrane-secreting) and shell gland (calcium-secreting) portions, but not in magnum (albumin secreting) tissue [12].
• Immunoreactive PTHrP was localized to the serosal membrane as well as the smooth muscle layer of serosal arterioles, suggesting that PTHrP may modulate vascular smooth muscle activity [12].
• In support of this hypothesis, synthetic chicken PTHrP (1-34)NH2 was found to relax the resting tension of isolated shell gland blood vessels in a dose-dependent manner [12].
• We localized the cycle-associated fluctuations in PTHrP mRNA levels to the shell gland serosa and smooth muscle layer [12].

Associations of PTHLH with chemical compounds

• The structure of chicken osteostatin or parathyroid hormone-related protein (PTHrP) (residues 107-139) containing an Ala/Thr substitution at the N-terminus was studied using two-dimensional proton NMR spectroscopy in an aqueous environment [13].
• Although all fractionated cells responded to PTHrP in culture by increasing thymidine incorporation and cAMP production and decreasing alkaline phosphatase activity, the magnitude of response was greatest in the proliferative chondrocytes [9].
• In TD, either induced by thiram or by genetic selection, normal levels of PTH/PTHrP receptor gene expression were observed up to 21 days post-hatch [3].
• However, PKA activation with dibutyryl cAMP mimicked PTHrP and blockade of PTHrP stimulation of PKA with H-89 inhibited the regulatory action of the factor [10].
• Mimicking the PTHrP stimulation either of PKC with 1-oleoyl 2-acetyl glycerol or of a Ca2+ pulse with 65 mM KCl did not lead to PTHrP-like effects on any of the four markers examined [10].

Regulatory relationships of PTHLH

• PTHrP expression in chick sternal chondrocytes is regulated by TGF-beta through Smad-mediated signaling [1].
• Expression of bone morphogenetic protein-2 and 4--7 was detected within the growth plate, and PTHrP inhibited the expression of bone morphogenetic protein-4 and 6 [9].
• Since PTHrP up-regulates BCL2 levels and prevents growth plate chondrocyte maturation and apoptosis, BCL2 mRNA levels were examined in irradiated growth plate chondrocytes, and a dose-dependent decrease was found [14].
• In contrast, a dominant negative Smad 3 completely inhibited PTHrP promoter stimulation by TGF-beta, but only partially blocked the effect of TGF-beta on PTHrP mRNA synthesis [1].

Other interactions of PTHLH

• These findings demonstrate that PTHrP is expressed in chondrocytes undergoing endochondral ossification, and show regulation, at least in part, by TGF-beta through Smad mediated signaling events [1].
• Bone morphogenetic proteins are considered likely intermediates in PTHrP signaling [9].
• These data demonstrate that although activation of PKC or Ca2+ signals is not required, the cylic AMP-dependent A kinase is required for PTHrP to regulate key hallmarks of GPC phenotype [10].
• While TGF-beta strongly inhibited all Wnts, PTHrP did not inhibit either Wnt8c or Wnt9a and had lesser effects on the expression of the other Wnts [15].

Analytical, diagnostic and therapeutic context of PTHLH

• The highest levels of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR-1), and Indian hedgehog (Ihh) expression were also found in the hypertrophic fractions B1 and B2 and not in the prehypertrophic fraction B3, as expected from in situ hybridization data on PTHR-1 expression in fetal rodent or chicken growth plates [16].
• Following coculture the PTHrP mRNA levels increased in the epiphyseal cells while the expression of type X collagen and Indian hedgehog transcripts decreased in growth plate chondrocytes [8].
• Immunohistochemistry of tissue sections showed that PTHrP protein was evident throughout the chick epiphysis [17].
• The importance of calcium in mediating radiation damage to growth plate chondrocytes was further demonstrated by the finding that the addition of 4.0 mM EGTA (a calcium chelator) to the cell cultures before irradiation prevented the decrease in PTHrP mRNA levels [14].
• PTHrP was detected by Western blotting as a band of 16,400 Da in extracts from hypertrophic chondrocytes, but not from proliferative cells [17].

References