Relationship between Histological Grade and Histopathological Appearance in Canine Mammary Carcinomas.

Canine mammary carcinomas are common tumours in female dogs and histopathological examination has an important role in identifying whether they are benign or malignant. The latest and most commonly used histological grading system was established by Peña et al. (2013) and is based on the extent of tubule formation, nuclear pleomorphism and number of mitoses. Before the establishment of this grading system, tumour size and classical histological indicators of malignancy such as lymphovascular invasion, infiltration into surrounding tissue, necrosis and presence of a micropapillary pattern were important predictors of biological behaviour. However, the system of Peña et al. does not consider tumour size or these histological features. Clarifying the association of these features and histological grade, especially in grade II and III carcinomas, is important. In this study, we confirmed that the system of Peña et al. is effective for predicting biological behaviour and that evaluation of histological features of malignancy reinforced histological grade, as determined by the system of Peña et al., especially in grade II carcinomas.

Cytomegalic Inclusion Disease caused by Cytomegalovirus Infection in the Salivary Glands of an African Hedgehog (Atelerix arbiventris).

Cytomegalic inclusion disease (CID) in the salivary gland of African hedgehogs (Atelerix arbiventris) has been reported before, and is suspected to reflect a cytomegalovirus infection. However, a recent ultrastructural study reported that African hedgehog CID reflected oncocytic metaplasia, mimicking a cytomegalovirus infection. We examined the submandibular and sublingual salivary glands of a 1-year-old male African hedgehog. Histologically, there were multiple foci composed of cytomegalic cells with intranuclear inclusion bodies. Ultrastructurally, viral particles (109-118 nm in diameter) were observed in the nuclei of the cytomegalic cells. There were numerous vesicles containing various numbers of enveloped viruses in the cytoplasm. We also attempted to detect viral DNA fragments by degenerate polymerase chain reaction and obtained amplicons of a predicted size. Phylogenetic analysis indicated that the virus is a betaherpesvirus, comparatively related to human and rodent cytomegaloviruses. The present study suggested that African hedgehog CIDs also include those caused by the cytomegalovirus.

Dielectric properties of fluorine substituted hydroxyapatite: the effect of the substitution on configuration of hydroxide ion chains.

Hydroxyapatite (HAp) [Ca5(PO4)3OH] is an extremely popular biomaterial. Moreover, HAp durability is well-known to be enhanced by fluoridation. We prepared fluoridated HAp (F-HAp; Ca5(PO4)3(OH)1-xFx) ceramics by substituting F- ions for OH- ions of HAp. F-substitution dependence of dielectric properties in F-HAp was measured to detect the configuration change of OH- ion chains. Dielectric relaxation of two kinds was observed. Each kind had a different relaxation time. Faster relaxation, which is associated with the reorientation motion of OH- ions, was only observed at the low F-substitution range (0 ≤x < 0.35). The relaxation strength decreased as the F-substitution increased. It became zero at x = 0.35, suggesting that F-substitution induces hydrogen bonds. One F- ion substituted for an OH- ion forms two hydrogen bonds with the two neighboring OH- ions and inhibits the motion of OH- ions, which results in some kind of ordered configuration in F-HAp. The configuration might be an origin that enhances the durability of the F-HAp.

Upregulation of PTH receptor mRNA expression by dexamethasone in UMR-106 osteoblast-like cells.

OBJECTIVES: Glucocorticoids influence receptor interactions of the parathyroid hormone (PTH) that are crucial for osteoblast function. As mechanisms linking receptor mRNA with glucocorticoids are incompletely understood, we investigated regulation of PTH receptor (PTH1R) mRNA expression in rat osteoblast-like UMR-106 cells by using dexamethasone (Dex), a synthetic glucocorticoid. MATERIALS AND METHODS: UMR-106 cells were exposed to 10(-8) to 10(-5) M Dex, while some cells were also exposed to a transcriptional inhibitor (DRB) for 24 h with or without Dex. PTH-stimulated cyclicAMP activities were measured by an enzyme-linked immunosorbent assay. PTH1R mRNA was determined by Northern analysis. Transcriptional activities were measured as heretogeneous nuclear PTH1R RNA and also as luciferase activity in constructs, including the PTH1R gene promoter. RESULTS: Dexamethasone dose-dependently increased PTH-stimulated adenylyl cyclase activity at 72 h. Dex markedly increased PTH1R mRNA accumulation, but did not change transcriptional activity. PTH1R mRNA stability was significantly increased by Dex in transcriptionally arrested cells. CONCLUSION: In osteoblast-like cells, Dex induced upregulation of PTH1R mRNA followed by increased functional PTH receptor expression. This was caused by posttranscriptional mechanisms increasing mRNA stability.

Statins and bone metabolism.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are potent inhibitors of cholesterol biosynthesis. Cholesterol-lowering therapy using statins significantly reduces the risk of coronary heart disease. However, extensive use of statins leads to increases of other undesirable as well as beneficial effects, so-called pleiotropic effects. With respect to these effects, statins augment the expression of bone morphogenetic protein-2, a potent simulator of osteoblast differentiation and its activity, and promote mineralization by cultured osteoblasts, indicating that statins have an anabolic effect on bone. Chronic administration of statins in ovariectomized (OVX) rats modestly increases bone mineral density (BMD) of cancellous bone but not of compact bone. In clinical studies, there are conflicting results regarding the clinical benefits of this therapy for the treatment of osteoporosis. Observational studies suggest an association between statin use and reduction in fracture risk. Clinical trials reported no effect of statin treatment on BMD in hip and spine, and on bone turnover. Statins also may influence oral osseous tissues. Administration of statins in combination with osteoporosis therapy appears to improve alveolar bone architecture in the mandibles of OVX rats with maxillary molar extraction. Statins continue to be considered as potential therapeutic agents for patients with osteoporosis and possibly with periodontal disease. Development of new statins that are more specific and potent for bone metabolism will greatly increase the usefulness of these drugs for the treatment of bone diseases.

Exotic radiation from a photonic crystal excited by an ultrarelativistic electron beam.

We report the observation of an exotic radiation (unconventional Smith-Purcell radiation) from a one-dimensional photonic crystal. The physical origin of the exotic radiation is direct excitation of the photonic bands by an ultrarelativistic electron beam. The spectrum of the exotic radiation follows photonic bands of a certain parity, in striking contrast to the conventional Smith-Purcell radiation, which shows solely a linear dispersion. Key ingredients for the observation are the facts that the electron beam is in an ultrarelativistic region and that the photonic crystal is finite. The origin of the radiation was identified by comparison of experimental and theoretical results.

High-transmission waveguide with a small radius of curvature at a bend fabricated by use of a circular photonic crystal.

A bent photonic crystal waveguide was fabricated by use of a lattice pattern of a circular photonic crystal that allowed high transmission for a broad band of wavelengths with a small radius of curvature at a bend. The waveguide was fabricated by use of alumina rods with a diameter of 3 mm. Windows of high transmission as a result of waveguiding were observed near 9 and 15 GHz. By measurement of the relative wave intensity [E]2 along the line defects, the propagation losses in the straight and the bent sections were estimated at 9.3 GHz to be 0.04 and 0.03 dB/mm, respectively.

Isotropic photonic gaps in a circular photonic crystal.

We investigated the optical properties of a circular photonic crystal (CPC) for which the distance between lattices was systematically distributed. The transmission spectra of CPC composed of alumina cylinders were examined in the frequency region from 0 to 20 GHz. We show that photonic gaps are obtained not only in CPCs but also in phase-shifted CPCs. The isotropic photonic gaps are evidenced by changes in the incident angle of a millimeter wave.

Parathyroid hormone (PTH) down-regulates PTH/PTH-related protein receptor gene expression in UMR-106 osteoblast-like cells via a 3',5'-cyclic adenosine monophosphate-dependent, protein kinase A-independent pathway.

Parathyroid hormone (PTH) regulates osteoblast function via a G protein-linked PTH/PTH-related protein (PTHrP) receptor. We have studied the mechanisms of PTH/PTHrP receptor gene repression by PTH in UMR-106 osteoblast-like cells. Inhibition of PTH/PTHrP receptor mRNA expression by rat (r) PTH(1-34) and Insulin-like growth factor-I (IGF-I) at 10(-7)M was significant at 1 h and 3 h, and maximal at 2 h and 6 h. A maximal decrease in receptor mRNA abundance by rPTH(1-34) and IGF-I was maintained for 24 h. Inhibition of receptor gene expression by rPTH(1-34) was mimicked in UMR-106 cells by the addition of forskolin (an adenylyl cyclase activator), or 8-(4-chlorophenylthio)-adenine 3',5'-cyclic monophosphate (8-pCPTcAMP; a cAMP analogue). Although H89, a selective protein kinase A (PKA) inhibitor, completely inhibited PKA activity stimulated by rPTH(1-34), forskolin or 8-pCPTcAMP, suppression of PTH/PTHrP receptor mRNA synthesis induced by these substances in UMR-106 cells was not affected by H89. In primary osteoblast cultures, rPTH(1-34) inhibited synthesis of PTH/PTHrP receptor mRNA irrespective of H89. The down-regulation effect of rPTH(1-34) was also unaltered by PD98059 (an extracellularly regulated kinase 1/2 mitogen-activated protein kinase pathway inhibitor). Pretreatment with cycloheximide, a protein synthesis inhibitor, did not alter the inhibition of PTH/PTHrP receptor mRNA expression by rPTH(1-34), indicating that receptor mRNA suppression does not require new protein synthesis. Transcriptional activation of PTH/PTHrP receptor gene promoter (U3P or U4P)-luciferase constructs was decreased by rPTH(1-34), forskolin and 8-pCPTcAMP irrespective of H89. Thus, PTH transcriptionally down-regulates PTH/PTHrP receptor gene expression in osteoblast-like cells via a cAMP-dependent, PKA-independent pathway.

Anabolic effects of recombinant human parathyroid hormone (1 - 84) and synthetic human parathyroid hormone (1 - 34) on the mandibles of osteopenic ovariectomized rats with maxillary molar extraction.

In rodent osteoporosis models such as ovariectomized (OVX) rats, intermittently administered human parathyroid hormone (hPTH) has an anabolic effect in vertebrae and long bones. In the present experiments, subcutaneously injected hPTH(1 - 34) or hPTH(1 - 84) dose- and time-dependently increased bone mineral density (BMD) as measured by dual energy X-ray absorptiometry in mandibles, L2 to L4 vertebrae and femurs of such rats. The highest dose (15.9 nmol/kg, s. c.) of either peptide given four times weekly for 10 weeks completely reversed the effects of overiectomy on BMD. Significant elevation in lumbar BMD after 10 weeks was observed with hPTH(1 - 34) or hPTH(1 - 84) at 1.1 nmol/kg, whereas hPTH(1 - 34) at 1.1 and 4.2 nmol/kg significantly increased BMD of the whole bone and the metaphysis of the femur and the diaphysis of the bone, respectively. In contrast, significant effects of hPTH(1 - 84) administration on BMD increase in the femur were observed at 4.2 and 15.9 nmol/kg in the whole bone and the metaphysis, and in the diaphysis, respectively. Maxillary molar extraction left mandibular BMD in rats with intact ovaries unchanged, but significantly decreased mandibular BMD in OVX rats. Administration of hPTH(1 - 84) for 10 weeks in OVX rats without or with extraction significantly increased BMD in the mandibular molar region at doses of 15.9 and 4.2 nmol/kg, respectively, indicating that efficacy was increased by extraction. A significant BMD increase in the molar region in OVX rats with extraction occurred at only 1.1 nmol/kg of hPTH(1 - 34) and 4.2 nmol/kg of hPTH(1 - 84). Also, BMD of the ramus region was increased by administration of both peptides to a lesser extent than that of the molar region in these rats. Thus, intermittent administration of hPTH, especially hPTH(1 - 34), has an anabolic effect on bone, particularly alveolar bone. Such treatment may increase alveolar bone mass in postmenopausal women with osteoporosis.

Loricrin keratoderma: a cause of congenital ichthyosiform erythroderma and collodion baby.

A group of hereditary palmoplantar keratodermas due to heterozygous mutation in the loricrin gene has recently been identified. Of five reported pedigrees, four presented as mutilating keratoderma with ichthyosis (variant Vohwinkel syndrome), and one as progressive symmetric erythrokeratoderma. We report a new Japanese pedigree of loricrin keratoderma. A 14-year-old male and his 11-year-old female sibling had both been born as collodion babies and were initially diagnosed as having non-bullous congenital ichthyosiform erythroderma, but later developed palmoplantar keratoderma with pseudoainhum. Their father was similarly affected. Direct sequencing of genomic DNA revealed a G residue insertion at codon 230-231 of the loricrin gene. Antibody studies confirmed the presence of mutant loricrin in the retained nuclei. We conclude that loricrin gene mutation may present as congenital ichthyosiform erythroderma, and should be included in the differential diagnosis of collodion baby.

Parathyroid hormone (PTH) suppresses rat PTH/PTH-related protein receptor gene promoter.

Parathyroid hormone (PTH) regulates osteoblasts via a G protein-linked PTH/PTH-related protein (PTHrP) receptor. PTH effects on PTH/PTHrP receptor gene expression were studied in UMR 106 osteoblast-like cells. In heterogeneous nuclear RNA and Northern analysis, PTH suppressed PTH/PTHrP receptor transcription. We cloned the 7-kb promoter region of the rat PTH/PTHrP receptor gene and transiently transfected chimeric deletion constructs containing the 5'-flanking region and the luciferase gene into UMR 106 cells. In transfected cells the minimal region for basal promoter activity was between positions -128 and +103. The 5'-flanking region of exon U1 contained several putative-binding sites for Sp1 and the myc-associated zinc finger protein (MAZ). The minimal PTH-suppressive region (PTHSR) was between +1 and +25 in exon U1, but the 5'-flanking region or Sp1 and MAZ-binding sites also were required for PTH-mediated repression. By gel mobility shift assay PTH markedly decreased binding of PTHSR-protein complex in UMR 106 cells. The mutation experiments showed that the most critical sequence for the repression of PTH was 5'-GGGGGAGGGGAG-3' (+1 to +12) of PTHSR. This represents the first characterization of a PTH-suppressive region of the PTH/PTHrP receptor gene in rat.

Stereoselectivity and species difference in plasma protein binding of KE-298 and its metabolites.

In vitro protein binding of KE-298 and its plasma metabolites, deacetyl-KE-298 (M-1) and S-methyl-KE-298 (M-2), was high in rat (>97%), dog (>89%) and human plasma (>99%), respectively. Human serum albumin (>93%) was the main protein involved in the binding to plasma proteins, while the binding to human serum globulins was low (16-33%). The binding of KE-298 and its metabolites in all species of plasma was stereoselective. The (+)-(S)-enantiomers of these compounds bound rat, dog and human plasma proteins to a greater extent than did the (-)-(R)-enantiomers, except that the case of KE-298 was opposite in rat plasma. The stereoselective plasma levels of these compounds in rats, dogs, or humans would likely be due to stereoselective differences in binding to plasma albumin. The protein binding of M-1 in adjuvant-induced arthritis rat plasma was >97%, and the stereoselectivity was similar to the case of normal rat plasma. KE-298 and its metabolites remarkably displaced [14C]warfarin, which bound on albumin in a solution of diluted rat serum albumin. Similarly, there was a displacement of [14C]warfarin in solutions of dog and human serum albumin, and concomitantly the displacement of [14C]diazepam. [3H]Digitoxin was not displaced by any of the enantiomers in each albumin solution. No stereoselectivity was found in displacement by enantiomers of the three compounds. These results suggest that stereoselective protein binding can be attributed to quantitative differences in binding to albumin rather than to the different binding sites.

[Minocycline-induced pneumonitis presenting as multiple ring-shaped opacities on chest CT, pathologically diagnosed bronchiolitis obliterans organizing pneumonia (BOOP)].

A 39-year old woman was admitted to our hospital because of cough and abnormal shadows on chest radiographs. She had been treated for 5 months for acne vulgaris with minocycline hydrochloride (MINO). Chest computed tomographic (CT) scans showed multiple ring-shaped opacities in both lungs. Bronchoalveolar lavage disclosed an increase in the total number of cells and a marked increase of lymphocytes. A lung specimen obtained by transbronchial lung biopsy (TBLB) was pathologically diagnosed as bronchiolitis obliterans organizing pneumonia (BOOP). Withdrawal of minocycline led to rapid remission without treatment. The clinical course and histological findings for TBLB suggested that this case was minocycline-induced BOOP. Several cases with minocycline-induced pneumonitis have been reported. However, there are few reported cases of minocycline-induced BOOP, the present case being only the second found in the literature.

Induction of collagenase-2 (matrix metalloproteinase-8) gene expression by interleukin-1beta in human gingival fibroblasts.

Collagenase-2 (matrix metalloproteinase-8 or MMP-8) is synthesized mainly by polymorphonuclear neutrophils and plays a crucial role in inflammatory periodontal tissue destruction. We tested the effect of interleukin(IL)-1beta, a proinflammatory cytokine, on collagenase-2 gene expression in cultured human gingival fibroblasts and also compared this effect with IL-1beta-induced changes in collagenase-1 and -3 gene expression. By a combination of reverse transcription-polymerase chain reaction and Southern analysis, IL-1beta was found to dose-dependently induce gene expression for collagenase-1, -2, and -3 in gingival fibroblasts. Although collagenase-2 mRNA was the least abundant among the three collagenase mRNAs tested in the cultured fibroblast system, addition of 1 ng/ml IL-1beta significantly increased collagenase-2 gene transcription within 6 h, and maximal stimulation was maintained for 12 to 48 h. Significant mRNA induction was observed with as little as 0.1 ng/ml IL-1beta. IL-1beta was also found to increase the stability of collagenase-2 mRNAs after transcription arrest was induced by an RNA polymerase inhibitor. Stimulation of collagenase-2 mRNA expression by IL-1beta was prevented by pretreatment with cycloheximide, an inhibitor of protein synthesis. These results indicate that IL-1beta increased mRNA expression for collagenases including collagenase-2 in gingival fibroblasts. The findings also suggest that enhancement of collagenase-2 mRNA expression by IL-1beta involves both protein synthesis and suppression of mRNA degradation.

Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells.

The cholesterol-lowering drug, simvastatin, is a pro-drug of a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and inhibits cholesterol synthesis in humans and animals. In addition, the bone effects of statins including simvastatin are being studied. We assessed the effects of simvastatin on osteoblastic differentiation in nontransformed osteoblastic cells (MC3T3-E1) and rat bone marrow cells. Simvastatin enhanced alkaline phosphatase (ALP) activity and mineralization in a dose- and time-dependent fashion. This stimulatory effect of the statin was observed at relatively low doses (significant at 10(-8) M and maximal at 10(-7) M). Northern blot analysis showed that the statin (10(-7) M) increased in bone morphogenetic protein-2 as well as ALP mRNA concentrations in MC3T3-E1 cells. Simvastatin (10(-7) M) slightly increased in type I collagen mRNA abundance throughout the culture period, whereas it markedly inhibited the gene expression of collagenase-1 between days 14 and 22 of culture. These results indicate that simvastatin has anabolic effects on bone through the promotion of osteoblastic differentiation, suggesting that it could be used for the treatment of common metabolic bone diseases such as osteoporosis.

Regulation of vitamin D-1alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney.

We investigated the effects of dexamethasone on vitamin D-1alpha-hydroxylase and -24-hydroxylase expression and on vitamin D receptor (VDR) content in the kidneys of mice fed either a normal (NCD) diet or a calcium- and vitamin D-deficient (LCD) diet for 2 weeks. For the last 5 days mice received either vehicle or dexamethasone (2 mg/kg per day s.c.). Dexamethasone significantly increased plasma calcium concentrations without changing plasma concentrations of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) in both NCD and LCD groups. Northern blot and enzyme activity analyses in NCD mice revealed that dexamethasone increased renal VDR mRNA expression modestly and greatly increased 24-hydroxylase mRNA abundance and enzyme activity, but did not affect 1alpha-hydroxylase mRNA abundance and enzyme activity. In mice fed an LCD diet, dexamethasone increased renal VDR mRNA expression 1.5-fold, decreased 1alpha-hydroxylase mRNA abundance (52%) and activity (34%), and markedly increased 24-hydroxylase mRNA abundance (16-fold) and enzyme activity (9-fold). Dexamethasone treatment did not alter functional VDR number (B(max) 125-141 fmol/mg protein) or ligand affinity (K(d) 0.13-0.10 nM) in LCD mice. Subcutaneous injections of 1,25(OH)(2)D(3) (0.24 nmol/kg per day for 5 days) into NCD mice strongly increased renal 24-hydroxylase mRNA abundance and enzyme activity, while there was no effect of dexamethasone on renal 24-hydroxylase expression in these mice. This may be due to overwhelming induction of 24-hydroxylase by 1,25(OH)(2)D(3). These findings suggest that glucocorticoid-induced osteoporosis is caused by direct action of the steroids on bone, and the regulatory effect of glucocorticoids on renal 25-hydroxyvitamin D(3) metabolism may be less implicated in the initiation and progression of the disease.

Coexistence of xeroderma pigmentosum with sarcoidosis and adenocarcinoma of the digestive organs.

Xeroderma pigmentosum has not been reported in association with any specific diseases except for skin malignancy. We observed a case of its coexistence with sarcoidosis and adenocarcinoma of the digestive organs, which has been reported only once in the past. A 54-year-old Japanese female with a variant type of xeroderma pigmentosum developed successively multiple lesions of basal cell carcinoma and squamous cell carcinoma on her face. Intensive metastasis studies led to the incidental detection of non-caseating epithelioid cell granulomas in one of the palpable right supraclavicular lymph nodes. Similar granulomas were also revealed in the excised tissue specimen of squamous cell carcinomas of her left cheek. She was also found to have bilateral hilar lymphadenopathy and chronic uveitis. Three years later, she died of colon adenocarcinoma and its liver metastasis.

Regulation of small intestinal transit by central nervous calcitonin receptor.

Salmon calcitonin (sCT) suppresses small intestinal transit (SIT) or motility, but the mechanism is not well understood. Bolus s. c. administration of a pharmacologic dose of sCT (140 IU/kg) to mice significantly decreased plasma calcium and phosphorus, and suppressed SIT from 1 to 8 h for plasma calcium and phosphorus or 20 h for SIT (respective maximal effects were seen at 5 h, between 2 and 8 h, and between 1 and 5 h). Significant SIT inhibition did not occur at doses smaller than 140 IU/kg. Reverse transcription-polymerase chain reactions and Southern analysis demonstrated high levels of calcitonin receptor mRNA in diencephalon and lung, moderate levels of mRNA in cerebellum, kidney, and muscle, and barely detectable amounts in cerebral cortex and thymus. No message was detectable in duodenum, jejunum, liver, testis, or heart. Specific binding of [125I] sCT was demonstrated in the diencephalon. Intracerebroventricular (i.c.v.) administration of sCT inhibited SIT time- and dose-dependently. Maximal inhibition was obtained at a dose of 4 IU/kg, 20 min after injection. Pretreatment with sCT (140 IU/kg s.c.) completely abolished inhibition of SIT by i.c.v. sCT (4 IU/kg). These results suggest that sCT binds to receptors in the central nervous system and inhibits small bowel transit.

Insulin-like growth factor I suppresses parathyroid hormone (PTH)/PTH-related protein receptor expression via a mitogen-activated protein kinase pathway in UMR-106 osteoblast-like cells.

Insulin-like growth factor I (IGF-I) is important in skeletal growth and has been implicated in the maintenance of bone integrity. PTH stimulates bone resorption through the G protein-linked PTH/PTH-related protein (PTHrP) receptor in osteoblasts. Using a heterogeneous nuclear RNA assay and Northern blot analysis, we showed that IGF-I inhibited expression of the gene for PTH/PTHrP receptor in a dose- and time-dependent fashion, but did not alter the stability of the receptor messenger RNA (mRNA) in UMR-106 osteoblast-like cells. IGF-I treatment for 48 h also caused a decrease in the receptor number to 45% of that in controls without affecting receptor affinity and in functional receptor expression to 50-60% of that in controls as measured by PTH-stimulated cAMP production. In MC3T3-E1 murine nontransformed osteoblasts, IGF suppressed receptor mRNA expression dose dependently. In UMR-106 cells, IGF-I induced the mitogen-activated protein (MAP) kinase pathway. The effect of IGF-I was blocked by PD98059, a specific inhibitor of the MAP kinase-activating kinase, but not by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. IGF-I inhibition of PTH/PTHrP receptor mRNA expression in UMR-106 cells was abrogated completely by pretreatment with cycloheximide, an inhibitor of protein synthesis. These findings indicate that IGF-I suppresses gene expression for PTH/PTHrP receptor via the MAP kinase pathway, and this inhibition is required for new protein synthesis in UMR-106 osteoblast-like cells.