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Biomedical subjects

T J Martin

Publications and source records attributed to T J Martin.

At least 19 recordsLinked to original sources
PubMed2006

Radioligand binding and functional responses of ligands for human recombinant adenosine A(3) receptors.

The binding and functional properties of adenosine receptor ligands were compared in Chinese hamster ovary cells transfected with human adenosine A(3) receptors. Inhibition of [(125)I]-aminobenzyl-5'-N-methylcarboamidoadenosine ([(125)I]-AB-MECA) binding by adenosine receptor ligands was examined in membrane preparations. Inhibition of forskolin-induced cAMP accumulation by agonists was measured using a cAMP enzyme immunoassay. The rank order of agonist potency for both assays was N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) > 5'-N-ethylcarboxamidoadenosine (NECA) > (-)-N(6)-[(R)-phenylisopropyl] adenosine (R-PIA) > 4-aminobenzyl-5'-N-methylcarboxamidoadenosine (AB-MECA) > N(6)-cyclopentyl adenosine (CPA) > adenosine. The radioligand binding rank order of antagonist potency was N-[9-chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide (MRS1220) > 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) > 8-phenyltheophylline (8-PT) > 8-(p-sulfophenyl)-theophylline (8-SPT). MRS1220 competitively inhibited the effect of IB-MECA on cAMP production, with a K(B) value of 0.35 nm. These data are characteristic of adenosine A(3) receptors. The absence of Mg(2+) and presence of guanosine 5'-(gamma-thio)triphosphate (GTPgammaS) significantly reduced agonist binding inhibition potency, indicating binding to high- and low-affinity states. The IB-MECA, NECA and R-PIA IC(50) values were greater for the cAMP assay than for radioligand binding, suggesting an efficient stimulus-response transduction pathway.

Adenosine↗
PubMed2006

Mechanisms involved in skeletal anabolic therapies.

Since parathyroid hormone (PTH) is the only proven anabolic therapy for bone, it becomes the benchmark by which new treatments will be evaluated. The anabolic effect of PTH is dependent upon intermittent administration, but when an elevated PTH level is maintained even for a few hours it initiates processes leading to new osteoclast formation, and the consequent resorption overrides the effects of activating genes that direct bone formation. Identification of PTH-related protein (PTHrP) production by cells early in the osteoblast lineage, and its action through the PTH1R upon more mature osteoblastic cells, together with the observation that PTHrP+/- mice are osteoporotic, all raise the possibility that PTHrP is a crucial paracrine regulator of bone formation. The finding that concurrent treatment with bisphosphonates impairs the anabolic response to PTH, adds to other clues that osteoclast activity is necessary to complement the direct effect that PTH has in promoting differentiation of committed osteoblast precursors. This might involve the generation of a coupling factor from osteoclasts that are transiently activated by receptor activator of nuclear factor-kappaB ligand (RANKL) in response to PTH. New approaches to anabolic therapies may come from the discovery that an activating mutation in the LRP5 gene is responsible for an inherited high bone mass syndrome, and the fact that this can be recapitulated in transgenic mice, whereas inactivating mutations result in severe bone loss. This has focused attention on the Wnt/frizzled/beta-catenin pathway as being important in bone formation, and proof of the concept has been obtained in experimental models.

Anabolic Agents↗
PubMed2006

Resistance to biotype 2 Russian wheat aphid (Homoptera: Aphididae) in two wheat lines.

Biotype 2 of the Russian wheat aphid, Diuraphis noxia (Mordvilko), was identified in the United States in 2003 and is virulent to all commercially available cultivars of winter wheat, Triticum aestivum L., that are resistant to biotype 1. We compared the development and reproduction of biotype 2 D. noxia at 21.7 +/- 0.12 degrees C on 'Trego' (PI 612576), a susceptible commercial cultivar, and on lines CI 2401 and 03GD1378027 that represent putative resistance sources. CI 2401 is a pure wheat line originating in the former USSR (Tajikistan), whereas 03GD1378027 is a USDA-ARS breeding line originally developed from crosses with a South African line that carried a large rye translocation conferring D. noxia resistance. Both lines previously showed resistance to biotype 1 and are currently being used in the development of D. noxia-resistant wheat cultivars. Both solitary apterous virginoparae of biotype 2 and their progeny experienced a reduction in survival and prolonged developmental times on CI 2401 and 03GD1378027 compared with Trego, but the former lines did not differ significantly from each other with respect to either measure of aphid performance. Progeny developed faster than did their foundress mothers on CI 2401 and Trego, but not on 03GD1378027. Mean foundress fecundity did not differ between CI 2401 and 03GD1378027 but was reduced on these lines relative to Trego. Foundresses also were more often found off plants of CI 2401 and 03GD1378027 than Trego. Estimates of intrinsic rate of increase were higher on Trego than on either CI 2401 or 03GD1378027, the latter two lines yielding similar values. The negative impacts of CI 2401 and 03GD1378027 on development and reproduction of biotype 2 indicate that these lines represent sources of resistance effective against this biotype.

Animals↗
PubMed2005

Effects of parathyroid hormone on Wnt signaling pathway in bone.

The Wnt signaling pathway has recently been demonstrated to play an important role in bone cell function. In previous studies using DNA microarray analyses, we observed a change in some of the molecular components of the canonical Wnt pathway namely, frizzled-1 (FZD-1) and axil, in response to continuous parathyroid hormone (PTH) treatment in rats. In the present study, we further explored other components of the Wnt signaling pathway in rat distal metaphyseal bone in vivo, and rat osteoblastic osteosarcoma cells (UMR 106) in culture. Several Wnt pathway components, including low-density lipoprotein-receptor-related protein 5 (LRP5), LRP6, FZD-1, Dickkopf-1 (Dkk-1), and Kremen-1 (KRM-1), were expressed in bone in vivo and in osteoblasts in vitro. Continuous exposure to PTH (1-38) both in vivo and in vitro upregulated the mRNA expression of LRP6 and FZD-1 and decreased LRP5 and Dkk-1. These effects in UMR 106 cells were associated with an increase in beta-catenin as measured by Western blots and resulted in functional activation (three to six-fold) of a downstream Wnt responsive TBE6-luciferase (TCF/LEF-binding element) reporter gene. Activation of the TBE6-luciferase reporter gene by PTH (1-38) in UMR 106 cells was inhibited by the protein kinase A (PKA) inhibitor, H89. Activation was mimicked by PTH (1-31), PTH-related protein (1-34), and forskolin, but both PTH (3-34) and (7-34) had no effect. These findings suggest that the effect of PTH on the canonical Wnt signaling pathway occurs at least in part via the cAMP-PKA pathway through the differential regulation of the receptor complex proteins (FZD-1/LRP5 or LRP6) and the antagonist (Dkk-1). Taken together, these results reveal a possible role for the Wnt signaling pathway in PTH actions in bone.

Animals↗
PubMed2004

Effects of 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) on the self-administration of cocaine, heroin, and cocaine/heroin combinations in rats.

Pharmacotherapies utilizing long-acting agonists and mixed function agonists-antagonists have been successful in the treatment of opiate addiction but no comparable treatment exists for cocaine abuse. Long-acting tropane analogues have been synthesized that could be candidates for such pharmacotherapies. 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) is one such compound that is a relatively selective dopamine (DA) transporter blocker that has a significantly longer duration of action than cocaine. The purpose of this study was to assess the effects of PTT on the intravenous self-administration of cocaine, heroin, or cocaine/heroin combinations. Groups of rats were trained to self-administer cocaine, heroin, or cocaine/heroin combinations using a within session dosing procedure in which three doses were available each session. PTT pretreatment reduced cocaine and cocaine/heroin combinations intake in a dose-dependent manner while having only minor effects on heroin intake. These results suggest that the neurobiological substrates of cocaine and heroin self-administration are different, and that these cocaine/heroin combinations may function more like cocaine alone, even when the dose of heroin in the mixture will function independently as a reinforcer. These results further support the potential use of long-acting dopamine reuptake inhibitors as pharmacotherapeutic adjuncts to a comprehensive treatment program for cocaine and cocaine/heroin abuse.

Analysis of Variance↗
PubMed2004

Immune, neuroendocrine, and somatic alterations in animal models of human heroin abuse.

We investigated immune, endocrine, and somatic alterations using two animal models of human heroin administration. In a heroin self-administration paradigm, we observed changes in immune function which suggest that the cycle of intermittent drug use is actually a stressor, which in turn not only exacerbates craving and drug-seeking behavior but also collaterally causes suppression of immune function and therefore susceptibility to disease. In another model of rats made physically dependent to heroin, we show that immune function is more broadly compromised, leading to evidence of infection, followed by chronic activation of innate immune function, cachexia, and weight loss.

Animals↗
PubMed2004

Paracrine regulation of osteoclast formation and activity: milestones in discovery.

The molecular and physiological mechanisms of control of osteoclast formation and activity have been explained with the discovery of three members of the Tumour Necrosis Factor superfamily. Receptor activator of NF-kappaB ligand (RANKL) is the type II membrane protein in cells of the osteoblastic lineage which interacts with its receptor, RANK, on hemopoietic precursors to promote osteoclast formation and maintain their viability and activity. The process is further regulated by the decoy receptor, osteoprotegerin (OPG), also produced by stromal/osteoblastic cells, and which binds to RANKL to prevent RANKL stimulation of osteoclast formation. These discoveries fulfilled predictions that came from more than 20 years of research in bone cell biology in predominantly rodent systems. The hypothesis that the osteoblast lineage directed osteoclast function introduced the concept of intercellular communication in bone. It needed new methods to be developed to test it, and there were many who contributed to this. With a number of identifiable milestones from the early 1980s on, a highly convincing case was made for the existence of what turned out to be RANKL and RANK. As it happened, OPG came first, and the background biological information was so instructive that it was obvious that OPG would lead to the final answer. By that stage the necessary methods were all in place, and in a short time all the key molecular regulators were identified. Ultimate proof of their physiological importance came from genetic experiments in mice.

Animals↗
PubMed2002

Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis.

Bone loss represents a major unsolved problem in rheumatoid arthritis (RA). The skeletal complications of RA consist of focal bone erosions and periarticular osteoporosis at sites of active inflammation, and generalized bone loss with reduced bone mass. New evidence indicates that osteoclasts are key mediators of all forms of bone loss in RA. TNF-alpha is one of the most potent osteoclastogenic cytokines produced in inflammation and is pivotal in the pathogenesis of RA. Production of tumor necrosis factor-alpha (TNF-alpha) and other proinflammatory cytokines in RA is largely CD4(+) T-cell dependent and mostly a result of interferon-gamma (IFN-gamma) secretion. Synovial T cells contribute to synovitis by secreting IFN-gamma and interleukin (IL)-17 as well as directly interacting with macrophages and fibroblasts through cell-to-cell contact mechanisms. Activated synovial T cells express both membrane-bound and soluble forms of receptor activator of NF-kappaB ligand (RANKL). In rheumatoid synovium, fibroblasts also provide an abundant source of RANKL. Furthermore, TNF-alpha and IL-1 target stromal-osteoblastic cells to increase IL-6, IL-11, and parathyroid hormone-related protein (PTHrP) production as well as expression of RANKL. In the presence of permissive levels of RANKL, TNF-alpha acts directly to stimulate osteoclast differentiation of macrophages and myeloid progenitor cells. In addition, TNF-alpha induces IL-1 release by synovial fibroblasts and macrophages, and IL-1, together with RANKL, is a major survival and activation signal for nascent osteoclasts. Consequently, TNF-alpha and IL-1, acting in concert with RANKL, can powerfully promote osteoclast recruitment, activation, and osteolysis in RA. The most convincing support for this hypothesis has come from in vivo studies of animal models. Protection of bone in the presence of continued inflammation in arthritic rats treated with osteoprotegerin (OPG) supports the concept that osteoclasts mediate bone loss, providing further evidence that OPG protects bone integrity by downregulating osteoclastogenesis and promoting osteoclast apoptosis. Modulation of the RANKL/OPG equilibrium in arthritis may provide additional skeletal benefits, such as chondroprotection. The nexus between T-cell activation, TNF-alpha overproduction, and the RANKL/OPG/RANK ligand-receptor system points to a unifying paradigm for the entire spectrum of skeletal pathology in RA. Strategies that address osteoclastic bone resorption will represent an important new facet of therapy for RA.

Arthritis, Rheumatoid↗
PubMed2002

Parathyroid hormone-related protein (PTHrP) production sites in elasmobranchs.

This study describes the distribution of parathyroid hormone-related protein (PTHrP) antigen and its mRNA in seven species of cartilaginous fish from six elasmobranch families. Antigen was detected using antibodies to synthetic human PTHrP and the mRNA with a riboprobe to human PTHrP gene sequence. The distribution pattern of PTHrP in the cartilaginous fish studied, reflected that observed in mammals but PTHrP further occurs in some sites unique to cartilaginous fish. Of particular note was the demonstration of PTHrP in the shark skeleton, which although considered not to contain bone, may form by a process similar to that forming the early stages of mammalian endochondral bone. The distribution of PTHrP in the elasmobranch skeleton resembled the distribution of PTHrP in the developing mammalian skeleton. Differences in the staining pattern between antisera to N-terminal PTHrP and mid-molecule PTHrP in the brain and pituitary suggested that the PTHrP molecule might be post-translationally processed in these tissues. The successful use of antibodies and a probe to human PTHrP in tissues from the early vertebrates examined in this study suggests that the PTHrP molecule is conserved from elasmobranchs to humans.

Animals↗
PubMed2001

Immunolocalization of vacuolar-type H+-ATPase, cathepsin K, matrix metalloproteinase-9, and receptor activator of NFkappaB ligand in odontoclasts during physiological root resorption of human deciduous teeth.

To investigate the cellular mechanisms of physiological root resorption in human deciduous teeth, the authors examined the immunocytochemical localization of vacuolar-type H+-ATPase, a lysosomal cysteine proteinase, cathepsin K, matrix metalloproteinase-9 (MMP-9), and receptor activator of NFKB ligand (RANKL) in odontoclasts. H+-ATPase, cathepsin K, and MMP-9 are the most important enzymes for decalcification of apatite crystals and degradation of type-I collagen. In addition, RANKL is one of the key regulatory molecules in osteoclast formation and functions. Odontoclasts developed extensive ruffled borders and clear zones apposed to the resorbing root dentine surfaces. On immunoelectron microscopy, the expression of vacuolar-type H+-ATPase was detected along the limiting membranes of pale vacuoles and the ruffled border membranes of odontoclasts. Cathepsin K in odontoclasts was localized within pale vacuoles, lysosomes, the extracellular canals of ruffled borders, and the underlying resorbing dentine surfaces. MMP-9 localization in odontoclasts was similar to those of cathepsin K. RANKL was detected in both mononuclear stromal cells and odontoclasts located on resorbing dentine surfaces. These results suggest that (1) odontoclasts are directly involved in decalcification of apatite crystals by active extrusion of proton ions mediated by H+-ATPase and (2) extracellular degradation of dentine type-I collagen by both cathepsin K and MMP-9, and (3) odontoclast differentiation and activity are regulated, at least in part, by RANKL, possibly produced by mononuclear stromal cells and odontoclasts themselves in the resorbing tissues. Thus, the cellular mechanisms of physiological root resorption appear to be quite similar to those of osteoclastic bone resorption.

Carrier Proteins↗
PubMed2001

mu Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine.

The efficacy of heroin metabolites for the stimulation of mu opioid receptor-mediated G-protein activation was investigated using agonist-stimulated [(35)S]guanosine-5'-O-(gamma-thio)-triphosphate binding. In rat thalamic membranes, heroin and its primary metabolite, 6-monoacetylmorphine (6-MAM), were more efficacious than morphine or morphine-6-beta D-glucuronide. This increased efficacy was not due to increased action of heroin and 6-MAM at delta receptors, as determined by competitive antagonism by naloxone, lack of antagonism by naltrindole, and competitive partial antagonism with morphine. In agreement with this interpretation, the same relative efficacy profile of heroin and its metabolites was observed at the cloned human mu opioid receptor expressed in C6 glioma cells. Moreover, these efficacy differences were GDP-dependent in a manner consistent with accepted mechanisms of receptor-mediated G-protein activation. The activity of heroin was attributed to in vitro deacetylation to 6-MAM, as confirmed by HPLC analysis. These results indicate that the heroin metabolite 6-MAM possesses higher efficacy than other heroin metabolites at mu opioid receptors, which may contribute to the higher efficacy of heroin compared with morphine in certain behavioral paradigms in vivo.

Analgesics, Opioid↗
PubMed2001

Stimulation of osteoprotegerin (OPG) gene expression by transforming growth factor-beta (TGF-beta). Mapping of the OPG promoter region that mediates TGF-beta effects.

Transforming growth factor-beta (TGF-beta) regulates osteoclastogenesis and osteoclast survival, in part through the induction of osteoprotegerin (OPG), a protein known to inhibit osteoclast formation and function. To explore the molecular basis of TGF-beta regulation of OPG expression, we evaluated the effects of TGF-beta on osteoclast formation, OPG protein secretion, mRNA expression, and gene transcription. The marked inhibitory effect of TGF-beta on osteoclast differentiation was confirmed in a co-culture model utilizing murine stromal/osteoblastic BALC cells and bone marrow hematopoietic precursors. This inhibition in osteoclast differentiation was preceded by a decrease in RANKL mRNA expression (5-fold) and a reciprocal increase in OPG mRNA (6.1-fold) and protein (7.1-fold) expression in BALC cells. At the promoter/transcriptional level, TGF-beta treatment resulted in a 3-10-fold increase in reporter gene activity directed by a 5.9-kilobase fragment of the human OPG promoter in transfection assays performed in UMR106 cells. The effect of TGF-beta was mimicked by TGF-beta2 and -beta3 but not by BMP-4, suggesting a TGF-beta signal-specific effect. Deletion analysis revealed that a 183-base pair region (-372 to -190) in the promoter was required for TGF-beta responsiveness, and this region was sufficient to confer TGF-beta inducibility to a heterologous (osteocalcin) minimal promoter. Substitution mutations that disrupted the Cbfa1- and/or Smad-binding elements present in the 183-base pair region resulted in a decrease in base-line expression and in the responsiveness to TGF-beta and Cbfa1. Collectively, these studies indicate the involvement and possible interaction of Cbfa1 and Smad proteins in mediating the effects of TGF-beta on OPG transcription.

Animals↗
PubMed2001

IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro.

IL-12, like IL-18, was shown to potently inhibit osteoclast formation in cultures of cocultures of murine osteoblast and spleen cells, as well as in adult spleen cells treated with M-CSF and receptor activator of NF-kappaB ligand (RANKL). Neither IL-12 nor IL-18 was able to inhibit RANKL-induced osteoclast formation in cultured RAW264.7 cells, demonstrating that IL-12, like IL-18, was unable to act directly on osteoclastic precursors. IL-12, like IL-18, was found to act by T cells, since depletion of T cells from the adult spleen cell cultures ablated the inhibitory action of IL-12 and addition of either CD4 or CD8 T cells from C57BL/6 mice to RANKL-stimulated RAW264.7 cultures permitted IL-12 or IL-18 to be inhibitory. Additionally, IL-12 was still able to inhibit osteoclast formation in cocultures with osteoblasts and spleen cells from either GM-CSF R(-/-) mice or IFN-gamma R(-/-) mice, indicating that neither GM-CSF nor IFN-gamma was mediating osteoclast inhibition in these cultures. Combined, IL-18 and IL-12 synergistically inhibited osteoclast formation at concentrations 20- to 1000-fold less, respectively, than when added individually. A candidate inhibitor could not be demonstrated using neutralizing Abs to IL-4, IL-10, or IL-13 or from mRNA expression profiles among known cytokine inhibitors of osteoclastogenesis in response to IL-12 and IL-18 treatment, although the unknown inhibitory molecule was determined to be secreted from T cells.

Animals↗
PubMed2001

Identification of signal transduction pathways and promoter sequences that mediate parathyroid hormone 1-38 inhibition of osteoprotegerin gene expression.

Osteoprotegerin (OPG), a secreted member of the tumor necrosis receptor superfamily, is a potent inhibitor of osteoclast formation and bone resorption. Parathyroid hormone (PTH), a potent inducer of osteoclast formation, suppresses OPG mRNA expression in vitro and in vivo. To determine the molecular basis of this inhibition, we analyzed the effects of PTH on the human OPG promoter (-5917 to +19) fused with beta-galactosidase reporter gene in stable and transient transfections into rat osteoblast-like UMR106 cells. The effect of PTH on OPG promoter expression was biphasic and concentration-dependent. PTH (1-100 nM) induced the transcriptional activity of the OPG promoter (1.7-fold) at 8 h followed by a gradual decrease with maximal inhibition (6.6-fold) at 24-48 h. To ascertain the signal transduction pathways mediating PTH (1-38) effects on OPG gene expression, we compared the effects of PTH with PTH analogs, parathyroid hormone-related protein 1-34 (PTHrP 1-34), forskolin, 3-isobutyl-1-methylxanthine (IBMX), dibutyryl cAMP, phorbol-12-myristate-13-acetate (PMA), thapsigargin and calcium ionophore A23187. PTH 1-31 and PTHrP 1-34, which stimulate the cAMP/PKA pathway, and other activators of cAMP/PKA, forskolin, IBMX, N(6), O(2')-dibityryl adenosine 3',5'-cyclic monophosphate (dibutyryl cAMP), all elicited a similar biphasic response on OPG promoter expression. PTH analogs PTH 3-34 and PTH 7-34, that do not stimulate cAMP production, had no effect on OPG expression. In contrast, phorbol-12-myristate-13-acetate (PMA), an activator of PKC, stimulated OPG promoter expression, while thapsigargin and calcium ionophore A23187, which increase intracellular Ca(2+), showed a dose-dependent inhibition of OPG promoter expression. To delineate the promoter sequences that mediate the inhibitory effects of PTH on OPG transcription, we analyzed systematic deletions of the OPG promoter for responsiveness in transient transfection assays. The major inhibitory effects of PTH were localized to 391 bp (-372 to +19) of the proximal promoter. Deletions of the promoter region led to a complete loss of responsiveness. Taken together, these results demonstrate that the inhibitory effects of PTH on OPG are mediated at the transcriptional level through cis elements in the proximal promoter. The similar biphasic response of OPG to PTH, PTH 1-31, PTHrP 1-34, forskolin, IBMX and dibutyryl cAMP suggests that PTH regulates OPG transcription via activation of the cAMP/PKA signal transduction pathway.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Effects of water temperature and salinity on parathyroid hormone-related protein in the circulation and tissues of elasmobranchs.

Parathyroid hormone-related protein (PTHrP) is a hypercalcemic factor in mammals. The PTHrP antigen has been localized in both bony and cartilaginous fish tissues. Sites of localization included gills, skin and kidney, organs involved in osmoregulation. Physiological and localization experiments were carried out in elasmobranchs to dissect PTHrP's possible role in osmoregulation. The effects of alterations in the external environment on PTHrP in sharks were examined by keeping juvenile animals under conditions of increased temperature or decreased salinity. There were no alterations in the PTHrP levels in either the circulation or tissues. Significant correlations between plasma PTHrP, electrolyte and urea levels were seen in the pretreatment samples. The localization of PTHrP by immunohistochemistry and in situ hybridization revealed conserved sites of distribution from elasmobranchs to mammals, including skin, kidney, muscle and skeleton.

Animals↗
PubMed2001

Fetal parathyroids are not required to maintain placental calcium transport.

We used Hoxa3 knockout mice and other mouse models to study the role of the fetal parathyroids in fetal calcium homeostasis. Hoxa3-null fetuses lack parathyroid glands, and absence of parathyroid hormone (PTH) was confirmed with a rodent PTH immunoradiometric assay. The ionized calcium level of Hoxa3-null fetuses was significantly lower than that of wild-type or heterozygous littermates or of the mother. Both the rate of placental calcium transfer and the plasma PTHrP level were normal in Hoxa3 mutants and their heterozygous siblings. Because we had previously observed an increase in placental calcium transfer in PTH/PTHrP receptor 1-null (Pthr1-null) fetuses, we assayed plasma PTHrP in those mice. Pthr1-null fetuses had plasma PTHrP levels 11-fold higher than those of their littermates. Northern analysis, immunohistochemical, and in situ hybridization studies of Pthr1-null fetuses indicated that liver and placenta had increased expression of PTHRP: In summary, loss of fetal parathyroids in Hoxa3-null fetuses caused marked hypocalcemia but did not alter placental calcium transfer or the circulating PTHrP level. The findings in the Pthr1-null fetuses indicate that several tissues may contribute to the circulating PTHrP level in fetal mice.

Animals↗