C-Terminal Parathyroid Hormone-Related Protein Inhibits Proliferation and Differentiation of Human Osteoblast-like Cells

Martı́nez, Marı́a Eugenia; Garcı́a-Ocaña, Adolfo; Sánchez, Miguel Ángel García; Medina, Sonia; Campo, T del; Valín, Álvaro; Sánchez-Cabezudo, M.; Esbrit, Pedro

doi:10.1359/jbmr.1997.12.5.778

Cited by 39 publications

(29 citation statements)

References 53 publications

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“…hOB cells were isolated from trabecular bone explants obtained from hip or knee samples discarded at the time of surgery on osteoarthritic patients, as described previously (13). The patients (three women and one man, ages 63-79 years) had no evidence of metabolic bone disorders.…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, PTHrP (107-139), a putative C-terminal PTHrP fragment (10), has also been shown to affect osteoblastic growth and differentiation, apparently by a protein kinase (PK) C-dependent mechanism (11)(12)(13)(14)(15)(16). The effects of this PTHrP Cterminal region appear to occur by its interaction with a specific receptor different from the type 1 PTH/PTHrP receptor (11,17).…”

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confidence: 99%

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Both N- and C-terminal Domains of Parathyroid Hormone-related Protein Increase Interleukin-6 by Nuclear Factor-κB Activation in Osteoblastic Cells

Guillén¹,

Martı́nez²,

Gortázar³

et al. 2002

Journal of Biological Chemistry

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Parathyroid hormone (PTH)-related protein (PTHrP) seems to affect bone resorption by interaction with bone cytokines, among them interleukin-6 (IL-6). Recent studies suggest that nuclear factor (NF)-B activation has an important role in bone resorption. We assessed whether the N-terminal fragment of PTHrP, and its C-terminal region, unrelated to PTH, can activate NF-B, and its relationship with IL-6 gene induction in different rat and human osteoblastic cell preparations. Here we present molecular data demonstrating that both PTHrP (1-36) and PTHrP (107-139) activate NF-B, leading to an increase in IL-6 mRNA, in these cells. Using anti-p65 and anti-p50 antibodies, we detected the presence of both proteins in the activated NF-B complex. This effect induced by either the N-or C-terminal PTHrP domain in osteoblastic cells appears to occur by different intracellular mechanisms, involving protein kinase A or intracellular Ca 2؉ /protein kinase C activation, respectively. However, the effect of each peptide alone did not increase further when added together. Our findings lend support to the hypothesis that the C-terminal domain of PTHrP, in a manner similar to its N-terminal fragment, might stimulate bone resorption. These studies also provide further insights into the putative role of PTHrP as a modulator of bone remodeling.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Both N- and C-terminal Domains of Parathyroid Hormone-related Protein Increase Interleukin-6 by Nuclear Factor-κB Activation in Osteoblastic Cells

Guillén¹,

Martı́nez²,

Gortázar³

et al. 2002

Journal of Biological Chemistry

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“…Whether osteoblasts are involved in this effect is, however, unclear. Limited and conflicting data suggest a role for C-terminal PTHrP fragments [e.g., PTHrP(107-111)] on osteoblast proliferation being either stimulatory or inhibitory, (3,4) but this issue needs more study.Nevertheless, we agree with Dr Martin that there are many unresolved issues regarding the auto-and paracrine role of PTHrP in osteoblast differentiation. Our study has addressed only a part of this role.…”

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confidence: 99%

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Full Length or Fragments in Hormone Studies?

Horst

Farih-Sips

Löwik

et al. 2006

Journal of Bone and Mineral Research

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We fully agree with Dr Martin that our study has specifically addressed the role of amino terminal fragments of PTH-related protein (PTHrP) and PTH in osteoblast differentiation. The effects of both fragments are mediated by the PTH/PTHrP type 1 receptor (PTHR1), and in concordance with extensive data, we did not observe a difference in effect of both hormone fragments. With respect to the role of PTHrP in osteoblast differentiation, many questions are still unresolved.First, PTHrP is a prepro-hormone subject to proteolytic processing.(1) Various N-terminal, midregional, and Cterminal fragments can be formed, each with its own proposed function. It is still unknown to what extent proteolytic processing of PTHrP occurs in osteoblasts and what is the dominant PTHrP fragment presented to the osteoblasts in vivo. This may well be full-length PTHrP as suggested by Dr Martin, but in our opinion, there is as yet no conclusive evidence for this.Second, whether and how C-terminal domains of PTHrP influence the biological activity of its N-terminal PTH-like domain is still largely unknown. This would require a detailed side-by side comparison of various naturally occurring N-terminal fragments of PTHrP [e.g., PTHrP(1-36), PTHrP(1-84), or PTHrP(1-139)]. These comparisons are currently lacking, most likely because of limited availability of the longer fragments.Third, whether PTHrP is having effects on osteoblast differentiation not mediated by the PTHR1 is a matter of debate. Some evidence for such a role for PTHrP comes from detailed comparison of the bone phenotype of PTHR1, PTHrP, and double null mice performed by Lanske et al.(2) The delay in vascular invasion in primary ossification centers observed in the PTHR1 null mice is not reversed in the double null mice, indicating that this effect of PTHrP is not mediated by the PTHR1. Whether osteoblasts are involved in this effect is, however, unclear. Limited and conflicting data suggest a role for C-terminal PTHrP fragments [e.g., PTHrP(107-111)] on osteoblast proliferation being either stimulatory or inhibitory, (3,4) but this issue needs more study.Nevertheless, we agree with Dr Martin that there are many unresolved issues regarding the auto-and paracrine role of PTHrP in osteoblast differentiation. Our study has addressed only a part of this role. There is a clear need for additional studies to clarify these unresolved functions of PTHrP in osteoblast biology.

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“…(13) PTHrP(107-111) also exerts inhibitory effects on osteoblastic proliferation and differentiation. (14) Not only are bone cells responsive to PTHrP, they also have the ability to express PTHrP mRNA and release PTHrP (reviewed elsewhere (2) ), as demonstrated in human and murine primary and clonal osteoblastic cell lines, (15)(16)(17)(18) rat fetal long bones, (19) and human trabecular bone explants. (16) PTHrP mRNA expression and protein levels are normally low in normal osteoblasts, but are up-regulated by PTH, phorbol esters, 1,25-dihydroxyvitamin D 3 and growth factors, and decreased by glucocorticoids.…”

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Two Human Osteoblast-like Osteosarcoma Cell Lines Show Distinct Expression and Differential Regulation of Parathyroid Hormone–Related Protein

Jemtland¹,

Rian²,

Olstad³

et al. 1999

Journal of Bone and Mineral Research

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Parathyroid hormone (PTH)-related protein (PTHrP) acts as a local regulator of osteoblast function via mechanisms that involve PTH/PTHrP receptors linked to protein kinase A (PKA) and C (PKC). However, the regulation of PTHrP production and mRNA expression in human osteoblasts is poorly understood. Here we have characterized alternative PTHrP mRNA 3 splicing variants, encoding PTHrP isoforms of 139, 141, and 173 amino acids, and studied the regulation of PTHrP and its mRNAs by activated PKA and PKC in two human osteoblast-like cell lines (KPDXM and TPXM). Using exon-specific Northern analysis and reverse transcriptase-coupled polymerase chain reaction, we identified mRNAs encoding PTHrP(1-139) and PTHrP(1-141) in both cell lines. PTHrP(1-139) mRNAs predominated in TPXM cells and PTHrP(1-173) mRNAs were only detected in TPXM cells. Activation of PKA or PKC resulted in different effects on PTHrP and its mRNAs in the two cell lines. In TPXM cells, peptide-specific immunoassays detected high basal levels of PTHrP, increasing by 2-fold in cell extracts and 4-fold in culture media at 7 h and 24 h after exposure to forskolin, respectively, paralleling changes in PTHrP mRNA expression. Phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA), a PKC activator, had no effect. In KPDXM cells, PTHrP was not detected in culture media under basal experimental conditions, and barely detectable amounts were present in cell extracts of TPA-treated cells, although the mRNA levels increased substantially in response to TPA. In the responsive cell lines, the effects on mRNA levels were dose dependent, and increased by 6.9-to 10.5-fold and 2.0-to 4.1-fold at 4 h in TPXM and KPDXM cells after exposure to 10 µM forskolin and 150 nM TPA, respectively. PTHrP mRNA levels then declined but were sustained above controls also at 12 h in both cell lines, albeit at considerably higher levels in TPXM cells. The different responsiveness to agents activating PKAand PKC-dependent pathways may depend on the cellular state of differentiation, or alternatively, cancer cell line-specific defects. Our data demonstrating distinct differences in mRNA species and the amounts of PTHrP produced by the two cell lines as compared with roughly equivalent overall mRNA levels may suggest that post-transcriptional mechanisms play an important role in limiting the production of intracellular and secreted PTHrPs in human osteoblastic cells. (J Bone Miner Res 1999;14:904-914)

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C-Terminal Parathyroid Hormone-Related Protein Inhibits Proliferation and Differentiation of Human Osteoblast-like Cells

Cited by 39 publications

References 53 publications

Both N- and C-terminal Domains of Parathyroid Hormone-related Protein Increase Interleukin-6 by Nuclear Factor-κB Activation in Osteoblastic Cells

Both N- and C-terminal Domains of Parathyroid Hormone-related Protein Increase Interleukin-6 by Nuclear Factor-κB Activation in Osteoblastic Cells

Full Length or Fragments in Hormone Studies?

Two Human Osteoblast-like Osteosarcoma Cell Lines Show Distinct Expression and Differential Regulation of Parathyroid Hormone–Related Protein

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