Medicine (St Vincent's) - Research Publications

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    G-CSF Receptor Deletion Amplifies Cortical Bone Dysfunction in Mice With STAT3 Hyperactivation in Osteocytes
    Isojima, T ; Walker, EC ; Poulton, IJ ; McGregor, NE ; Wicks, IP ; Gooi, JH ; Martin, TJ ; Sims, NA (WILEY, 2022-10)
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    Osteoclast Inhibitory Lectin, an Immune Cell Product That Is Required for Normal Bone Physiology in Vivo
    Kartsogiannis, V ; Sims, NA ; Quinn, JMW ; Ly, C ; Cipetic, M ; Poulton, IJ ; Walker, EC ; Saleh, H ; McGregor, NE ; Wallace, ME ; Smyth, MJ ; Martin, TJ ; Zhou, H ; Ng, KW ; Gillespie, MT (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2008-11-07)
    Osteoclast inhibitory lectin (OCIL or clrb) is a member of the natural killer cell C-type lectins that have a described role mostly in autoimmune cell function. OCIL was originally identified as an osteoblast-derived inhibitor of osteoclast formation in vitro. To determine the physiological function(s) of OCIL, we generated ocil(-/-) mice. These mice appeared healthy and were fertile, with no apparent immune function defect, and phenotypic abnormalities were limited to bone. Histomorphometric analysis revealed a significantly lower tibial trabecular bone volume and trabecular number in the 10- and 16-week-old male ocil(-/-) mice compared with wild type mice. Furthermore, ocil(-/-) mice showed reduced bone formation rate in the 10-week-old females and 16-week-old males while Static markers of bone formation showed no significant changes in male or female ocil(-/-) mice. Examination of bone resorption markers in the long bones of ocil(-/-) mice indicated a transient increase in osteoclast number per unit bone perimeter. Enhanced osteoclast formation was also observed when either bone marrow or splenic cultures were generated in vitro from ocil(-/-) mice relative to wild type control cultures. Loss of ocil therefore resulted in osteopenia in adult mice primarily as a result of increased osteoclast formation and/or decreased bone formation. The enhanced osteoclastic activity led to elevated serum calcium levels, which resulted in the suppression of circulating parathyroid hormone in 10-week-old ocil(-/-) mice compared with wild type control mice. Collectively, our data suggest that OCIL is a physiological negative regulator of bone.
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    Parathyroid hormone receptors in GtoPdb v.2021.3
    Bisello, A ; Chorev, M ; Friedman, PA ; Gardella, T ; Hills, R ; Jueppner, H ; Martin, TJ ; Nissenson, RA ; Potts, Jr., JT ; Silve, C ; Usdin, TB ; Vilardaga, J-P (Edinburgh University Library, 2021-09-02)
    The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [49]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (84 amino acids), and PTHrP (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids). [125I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-Gs complex has been resolved by cryo-electron microscopy [147]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [34].
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    Parathyroid hormone receptors in GtoPdb v.2021.2
    Bisello, A ; Chorev, M ; Friedman, PA ; Gardella, T ; Hills, R ; Jueppner, H ; Martin, TJ ; Nissenson, RA ; Potts, Jr., JT ; Silve, C ; Usdin, TB ; Vilardaga, J-P (Edinburgh University Library, 2021-06-25)
    The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [49]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (84 amino acids), and PTHrP (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids). [125I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analog (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-Gs complex has been resolved by cryo-electron microscopy [147]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [34].
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    Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors.
    Udagawa, N ; Takahashi, N ; Katagiri, T ; Tamura, T ; Wada, S ; Findlay, DM ; Martin, TJ ; Hirota, H ; Taga, T ; Kishimoto, T ; Suda, T (Rockefeller University Press, 1995-11-01)
    We reported that interleukin (IL) 6 alone cannot induce osteoclast formation in cocultures of mouse bone marrow and osteoblastic cells, but soluble IL-6 receptor (IL-6R) strikingly triggered osteoclast formation induced by IL-6. In this study, we examined the mechanism of osteoclast formation by IL-6 and related cytokines through the interaction between osteoblastic cells and osteoclast progenitors. When dexamethasone was added to the cocultures, IL-6 could stimulate osteoclast formation without the help of soluble IL-6R. Osteoblastic cells expressed a very low level of IL-6R mRNA, whereas fresh mouse spleen and bone marrow cells, both of which are considered to be osteoclast progenitors, constitutively expressed relatively high levels of IL-6R mRNA. Treatment of osteoblastic cells with dexamethasone induced a marked increase in the expression of IL-6R mRNA. By immunoblotting with antiphosphotyrosine antibody, IL-6 did not tyrosine-phosphorylate a protein with a molecular mass of 130 kD in osteoblastic cells but did so in dexamethasone-pretreated osteoblastic cells. Osteoblastic cells from transgenic mice constitutively expressing human IL-6R could support osteoclast development in the presence of human IL-6 alone in cocultures with normal spleen cells. In contrast, osteoclast progenitors in spleen cells from transgenic mice overexpressing human IL-6R were not able to differentiate into osteoclasts in response to IL-6 in cocultures with normal osteoblastic cells. These results clearly indicate that the ability of IL-6 to induce osteoclast differentiation depends on signal transduction mediated by IL-6R expressed on osteoblastic cells but not on osteoclast progenitors.
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    PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway
    Martin, TJ (FRONTIERS MEDIA SA, 2022-01-19)
    After the initial signaling action of parathyroid hormone (PTH) on bone was shown to be activation of adenylyl cyclase, its target was found to be cells of the osteoblast lineage, to the exclusion of osteoclasts and their precursors. This led to the view that the osteoblast lineage regulated osteoclast formation, a proposal that was established when the molecular mechanisms of osteoclast formation were discovered. This is in addition to the effect of PTH1Rv signaling throughout the osteoblast differentiation process to favour the formation of bone-forming osteoblasts. Initial signaling in the PTH target cells through cAMP and protein kinase A (PKA) activation is extremely rapid, and marked by an amplification process in which the later event, PKA activation, precedes cAMP accumulation in time and is achieved at lower concentrations. All of this is consistent with the existence of "spare receptors", as is the case with several other peptide hormones. PTH-related protein (PTHrP), that was discovered as a cancer product, shares structural similarity with PTH in the amino-terminal domain that allows the hormone, PTH, and the autocrine/paracrine agent, PTHrP, to share actions upon a common G protein coupled receptor, PTH1R, through which they activate adenylyl cyclase with equivalent potencies. Studies of ligand-receptor kinetics have revealed that the PTH/PTH1R ligand-receptor complex, after initial binding and adenylyl cyclase activation at the plasma membrane, is translocated to the endosome, where adenylyl cyclase activation persists for a further short period. This behavior of the PTH1R resembles that of a number of hormones and other agonists that undergo such endosomal translocation. It remains to be determined whether and to what extent the cellular effects through the PTH1R might be influenced when endosomal is added to plasma membrane activation.
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    Secretion of prostaglandins as bone-resorbing agents by renal cortical carcinoma in culture.
    Atkins, D ; Ibbotson, KJ ; Hillier, K ; Hunt, NH ; Hammonds, JC ; Martin, TJ (Springer Science and Business Media LLC, 1977-11)
    Fragments of human renal carcinoma tissue have been co-cultured with mouse calvaria. In 9/13 cases significant bone resorption occurred whilst in no case did control kidney cause significant resorption. When bone resorption did occur, it could be reduced by inclusion of indomethacin in the culture medium. In some cases when theophylline was included in culture medium to prevent cyclic AMP breakdown, there was enhancement of tumour-induced bone resorption. Control studies without tumour showed that none of the experimental treatments had a direct effect on bone. Radioimmunoassay of prostaglandin E (PGE) levels in pooled culture media showed that tumour fragments produced appreciable amounts of PGE, and that this production was lowered by indomethacin and increased by theophylline. It is concluded that the bone resorption induced by these tumours is due to a prostaglandin, and that prostaglandin production may be controlled by changes in cyclic AMP metabolism.
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    Alternative promoter usage and mRNA splicing pathways for parathyroid hormone-related protein in normal tissues and tumours.
    Southby, J ; O'Keeffe, LM ; Martin, TJ ; Gillespie, MT (Springer Science and Business Media LLC, 1995-09)
    The parathyroid hormone-related protein (PTHrP) gene consists of nine exons and allows the production of multiple PTHrP mRNA species via the use of three promoters and 5' and 3' alternative splicing; as a result of 3' alternative splicing one of three protein isoforms may be produced. This organisation has potential for tissue-specific splicing patterns. We examined PTHrP mRNA expression and splicing patterns in a series of tumours and normal tissues, using the sensitive reverse transcription-polymerase chain reaction (RT-PCR) technique. Use of promoter 3 and mRNA specifying the 141 amino acid PTHrP isoform were detected in all samples. Transcripts encoding the 139 amino acid isoform were detected in all but two samples. Use of promoters 1 and 2 was less widespread as was detection of mRNA encoding the 173 amino acid isoform. While different PTHrP splicing patterns were observed between tumours, no tissue- or tumour-specific transcripts were detected. In comparing normal and tumour tissue from the same patient, an increase in the number of promoters utilised was observed in the tumour tissue. Furthermore, mRNA for the PTH/PTHrP receptor was detected in all samples, thus the PTHrP produced by these tumours may potentially act in an autocrine or paracrine fashion.
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    Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction.
    Kobayashi, K ; Takahashi, N ; Jimi, E ; Udagawa, N ; Takami, M ; Kotake, S ; Nakagawa, N ; Kinosaki, M ; Yamaguchi, K ; Shima, N ; Yasuda, H ; Morinaga, T ; Higashio, K ; Martin, TJ ; Suda, T (Rockefeller University Press, 2000-01-17)
    Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF-dependent bone marrow macrophages (M-BMM phi) appeared within 3 d. Tartrate-resistant acid phosphatase-positive osteoclasts were also formed when M-BMM phi were further cultured for 3 d with mouse tumor necrosis factor alpha (TNF-alpha) in the presence of M-CSF. Osteoclast formation induced by TNF-alpha was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti-RANK (ODF/RANKL receptor) antibody. Experiments using M-BMM phi prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-alpha. Osteoclasts induced by TNF-alpha formed resorption pits on dentine slices only in the presence of IL-1alpha. These results demonstrate that TNF-alpha stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL-RANK system. TNF-alpha together with IL-1alpha may play an important role in bone resorption of inflammatory bone diseases.
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    Calcitonin-responsive adenylate cyclase in a calcitonin-producing human cancer cell line.
    Hunt, NH ; Ellison, M ; Underwood, JC ; Martin, TJ (Springer Science and Business Media LLC, 1977-06)
    A calcitonin-responsive adenylate cyclase has been found in a cell line of a poorly differentiated bronchial carcinoma (BEN cells). The cells have previously been shown to secrete an immunoreactive form of calcitonin in culture. Salmon calcitonin (SCT), porcine calcitonin (PCT) and human calcitonin (CT-M) all stimulated adenylate cyclase activity in particulate preparations. CT-M sulphoxide had little effect. The concentrations of the calcitonins required for half the maximum activation of adenylate cyclase were 6-8, 18 and 90 nm respectively. SCT (30pm) and CT-M (60 pm) increased the intracellular concentration of cyclic AMP from 11-2+/-0-2 (s.e.) to 18-2+/-0-2 and 16-7+/-0-2 respectively over a 2-5-min period. SCT (labelled with 125I) bound to particulate preparations of Ben cells, and competition for binding occurred with unlabelled SCT and CT-M. The concentration of SCT required for half the maximum inhibition of [125I]SCT binding was 11 nm. CT-M sulphoxide inhibited only at high concentration (3 micron). The characteristics of the adenylate cyclase response to SCT did not change over the period between cell adhesion (after subculture) and confluence. However, pre-incubation of cells for 4 h with SCT (150 nm) abolished the subsequent adenylate cyclase response of particulate preparations to further hormone. The practical difficulties encountered in purifying and quantifying the large-mol.-wt. form of CT-M secreted by BEN cells has precluded direct investigation of the potential relationship between hormone secretion and the occurrence of the calcitonin receptor. This relationship is discussed in terms of its possible biological significance.