Glucocorticoid-Induced Bone Fragility Is Prevented in Female Mice by Blocking Pyk2/Anoikis Signaling.

Abstract:

:Excess of glucocorticoids (GCs) is a leading cause of bone fragility, and therapeutic targets are sorely needed. We report that genetic deletion or pharmacological inhibition of proline-rich tyrosine kinase 2 (Pyk2) prevents GC-induced bone loss by overriding GC effects of detachment-induced bone cell apoptosis (anoikis). In wild-type or vehicle-treated mice, GCs either prevented osteoclast apoptosis or promoted osteoblast/osteocyte apoptosis. In contrast, mice lacking Pyk2 [knockout (KO)] or treated with Pyk2 kinase inhibitor PF-431396 (PF) were protected. KO or PF-treated mice were also protected from GC-induced bone resorption, microarchitecture deterioration, and weakening of biomechanical properties. In KO and PF-treated mice, GC increased osteoclasts in bone and circulating tartrate-resistant acid phosphatase form 5b, an index of osteoclast number. However, bone surfaces covered by osteoclasts and circulating C-terminal telopeptides of type I collagen, an index of osteoclast function, were not increased. The mismatch between osteoclast number vs function induced by Pyk2 deficiency/inhibition was due to osteoclast detachment and anoikis. Further, GC prolongation of osteoclast lifespan was absent in KO and PF-treated osteoclasts, demonstrating Pyk2 as an intrinsic osteoclast-survival regulator. Circumventing Pyk2 activation preserves skeletal integrity by preventing GC effects on bone cell survival (proapoptotic for osteoblasts/osteocytes, antiapoptotic for osteoclasts) and GC-induced bone resorption. Thus, Pyk2/anoikis signaling as a therapeutic target for GC-induced osteoporosis.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Sato AY,Cregor M,McAndrews K,Li T,Condon KW,Plotkin LI,Bellido T

doi

10.1210/en.2019-00237

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

1659-1673

issue

7

eissn

0013-7227

issn

1945-7170

pii

5487989

journal_volume

160

pub_type

杂志文章
  • Rat 17 beta-hydroxysteroid dehydrogenase type 1: primary structure and regulation of enzyme expression in rat ovary by diethylstilbestrol and gonadotropins in vivo.

    abstract::17 beta-Hydroxysteroid dehydrogenase (17HSD) catalyzes the reversible conversion of estrone into estradiol. The complementary DNA (cDNA) coding for rat 17HSD type 1 was cloned from a commercial rat ovarian cDNA library, using human 17HSD type 1 cDNA as a probe. The nucleotide sequence extends for 1160 basepairs (bp), ...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.135.4.7925110

    authors: Ghersevich S,Nokelainen P,Poutanen M,Orava M,Autio-Harmainen H,Rajaniemi H,Vihko R

    更新日期:1994-10-01 00:00:00

  • Temporal silencing of an androgenic gland-specific insulin-like gene affecting phenotypical gender differences and spermatogenesis.

    abstract::Androgenic glands (AGs) of the freshwater prawn Macrobrachium rosenbergii were subjected to endocrine manipulation, causing them to hypertrophy. Transcripts from these glands were used in the construction of an AG cDNA subtractive library. Screening of the library revealed an AG-specific gene, termed the M. rosenbergi...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2008-0906

    authors: Ventura T,Manor R,Aflalo ED,Weil S,Raviv S,Glazer L,Sagi A

    更新日期:2009-03-01 00:00:00

  • Acetylcholine Modulates the Hormones of the Growth Hormone/Insulinlike Growth Factor-1 Axis During Development in Mice.

    abstract::Pituitary growth hormone (GH) and insulinlike growth factor (IGF)-1 are anabolic hormones whose physiological roles are particularly important during development. The activity of the GH/IGF-1 axis is controlled by complex neuroendocrine systems including two hypothalamic neuropeptides, GH-releasing hormone (GHRH) and ...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2017-03175

    authors: Lecomte MJ,Bertolus C,Ramanantsoa N,Saurini F,Callebert J,Sénamaud-Beaufort C,Ringot M,Bourgeois T,Matrot B,Collet C,Nardelli J,Mallet J,Vodjdani G,Gallego J,Launay JM,Berrard S

    更新日期:2018-04-01 00:00:00

  • Differential involvement of the actin cytoskeleton in differentiation and mitogenesis of thyroid cells: inactivation of Rho proteins contributes to cyclic adenosine monophosphate-dependent gene expression but prevents mitogenesis.

    abstract::In thyroid epithelial cells, TSH via cAMP induces a rounding up of the cells associated with actin stress fiber disruption, expression of differentiation genes and cell cycle progression. Here we have evaluated the role of small G proteins of the Rho family and their impact on the actin cytoskeleton in these different...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2005-0329

    authors: Fortemaison N,Blancquaert S,Dumont JE,Maenhaut C,Aktories K,Roger PP,Dremier S

    更新日期:2005-12-01 00:00:00

  • Prolactin synthesis in bovine pituitary: no evidence for regulation by estrogen in vivo.

    abstract::Protein synthesis in bovine pituitaries was measured by incubation of tissue slices with radioactive amino acids, followed by gel electrophoresis. PRL and GH syntheses were estimated by determining the amount of radioactivity comigrating with standards of these hormones. Pituitary tissue removed from adult animals dem...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-109-2-576

    authors: Baxter LA,Gorski J

    更新日期:1981-08-01 00:00:00

  • Inhibin suppresses luteinizing hormone (LH)-releasing hormone self-priming: direct action on follicle-stimulating hormone secretion and opposition of estradiol-enhanced LH secretion.

    abstract::Previous studies have suggested that the ovary produces a factor that maintains the pituitary in a state of low LHRH responsiveness that must be overcome by the self-priming action of LHRH. To determine the role of inhibin in maintaining low LHRH responsiveness in pituitaries of diestrous female rats, endogenous inhib...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.130.3.1537310

    authors: Culler MD

    更新日期:1992-03-01 00:00:00

  • Uptake of triiodothyroacetic acid and its effect on thyrotropin secretion in cultured anterior pituitary cells.

    abstract::The uptake of [125I]triiodothyroacetic acid ([125I]Triac) in anterior pituitary cells was investigated and compared with that of [125I]T3. Furthermore, the effects of Triac, T3, and T4 on TSH release were compared. Cells isolated from adult male Wistar rats were cultured for 3 days in medium with 10% fetal calf serum....

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.135.6.7988460

    authors: Everts ME,Visser TJ,Moerings EP,Docter R,van Toor H,Tempelaars AM,de Jong M,Krenning EP,Hennemann G

    更新日期:1994-12-01 00:00:00

  • Quantitative analysis of estrogen receptor proteins in rat mammary gland.

    abstract::Estrogen receptor alpha and beta proteins (ERalpha and ERbeta) at various stages of development of the rat mammary gland were quantified by Western blotting. ERalpha and ERbeta recombinant proteins were used as standards, and their molar concentrations were measured by ligand binding assays. In 3-week-old pregnant, la...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.142.7.8260

    authors: Saji S,Sakaguchi H,Andersson S,Warner M,Gustafsson J

    更新日期:2001-07-01 00:00:00

  • Localization of G protein alpha-subunits in the human fetal adrenal gland.

    abstract::The aim of the present study was to investigate the presence and localization of the main G protein alpha-subunits in the human fetal adrenal gland during the second trimester of gestation. Immunofluorescence studies conducted on sections from frozen glands obtained immediately after therapeutic abortion indicated tha...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.141.12.7834

    authors: Breault L,Chamoux E,Lehoux JG,Gallo-Payet N

    更新日期:2000-12-01 00:00:00

  • Differential gene expression of cytochrome P450 11beta-hydroxylase in rat adrenal cortex after in vivo activation.

    abstract::In situ hybridization histochemistry was used to monitor the expression of 3beta-hydroxysteroid dehydrogenase, delta4-isomerase (3betaHSD) and cytochrome P450 11beta-hydroxylase (P45011beta) messenger RNA (mRNA) in adult rat adrenals after stimulation in vivo. In Exp 1, adrenals were collected from rats injected with ...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.138.6.5157

    authors: Engeland WC,Levay-Young BK,Rogers LM,Fitzgerald D

    更新日期:1997-06-01 00:00:00

  • Role of estradiol as a biological amplifier of gonadotropin action in the ovary: in vitro studies using swine granulosa cells and homologous lipoproteins.

    abstract::Swine granulosa cells cultured under serum-free conditions in vitro exhibit significant responsivity to the stimulatory actions of estradiol (E2) and FSH or LH. Under these conditions, granulosa cells harvested from either immature or mature Graafian follicles synthesized significantly increased quantities of progeste...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-114-6-2312

    authors: Veldhuis JD,Gwynne JT,Strauss JF 3rd,Demers LM

    更新日期:1984-06-01 00:00:00

  • Effects of polypeptide YY(3-36) upon luteinizing hormone-releasing hormone and gonadotropin secretion in prepubertal rats: in vivo and in vitro studies.

    abstract::Polypeptide YY(3-36) (PYY(3-36)) is a gastrointestinal secreted molecule, agonist of neuropeptide Y (NPY) receptor subtypes Y2 and Y5, recently involved in the control of food intake. Notably, several factors with key roles in energy homeostasis conduct pleiotropic effects upon the reproductive axis. However, whether ...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2004-0858

    authors: Fernandez-Fernandez R,Aguilar E,Tena-Sempere M,Pinilla L

    更新日期:2005-03-01 00:00:00

  • The role of gonadotropin-releasing hormone in murine preimplantation embryonic development.

    abstract::Previous studies have established the presence of an extrahypothalamic GnRH in a variety of tissues. GnRH receptor is known to be present in the placenta, which produces and secretes the decapeptide from the very early stages of placentation. We hypothesized that GnRH may play a role in the preimplantation development...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.140.8.6899

    authors: Raga F,Casañ EM,Kruessel J,Wen Y,Bonilla-Musoles F,Polan ML

    更新日期:1999-08-01 00:00:00

  • Tuberoinfundibular peptide of 39 residues is activated during lactation and participates in the suckling-induced prolactin release in rat.

    abstract::Tuberoinfundibular peptide of 39 residues (TIP39) and the PTH-2 receptor (PTH2R) constitute a peptide-receptor neuromodulator system. Based on the abundance of TIP39 fibers and axonal terminals as well as PTH2R-containing neurons and their processes in the hypothalamic para- and periventricular and arcuate nuclei TIP3...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2010-0767

    authors: Cservenák M,Bodnár I,Usdin TB,Palkovits M,Nagy GM,Dobolyi A

    更新日期:2010-12-01 00:00:00

  • Stress-induced secretion of adrenocorticotropin in rats is inhibited by administration of antisera to ovine corticotropin-releasing factor and vasopressin.

    abstract::Intact handled rats were pretreated with the immunoglobulin G fractions from normal rabbit serum or antisera to ovine corticotropin-releasing factor (CRF) and/or vasopressin and subjected to restraint or formalin stress. The formalin-induced rise in plasma ACTH was reduced to 28% in rats pretreated with anti-CRF, to 5...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-116-3-966

    authors: Linton EA,Tilders FJ,Hodgkinson S,Berkenbosch F,Vermes I,Lowry PJ

    更新日期:1985-03-01 00:00:00

  • Tumor growth inhibition by indomethacin in a mouse model of human medullary thyroid cancer: implication of cyclooxygenases and 15-hydroxyprostaglandin dehydrogenase.

    abstract::Medullary thyroid cancer (MTC) is a C cell neoplasm-secreting calcitonin. Surgery remains the only treatment as the primary tumor and metastases resist radio- and chemotherapies. MTC produces high amounts of prostaglandins (PGs). Nonsteroidal antiinflammatory drugs have an antitumoral effect, generally related to the ...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2003-0915

    authors: Quidville V,Segond N,Pidoux E,Cohen R,Jullienne A,Lausson S

    更新日期:2004-05-01 00:00:00

  • Initial events in phorbol ester binding to GH4C1 rat pituitary cells.

    abstract::Phorbol ester receptors in GH4C1 rat pituitary cells have been studied using [3H]phorbol 12,13-dibutyrate (PDBu). Binding to intact cells was of higher affinity at 37 C than at 4 C (Kd, approximately 8 or approximately 34 nM, respectively). The dissociation rate (measured at 4 C) of PDBu from cells equilibrated at 37 ...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-117-6-2293

    authors: Jaken S

    更新日期:1985-12-01 00:00:00

  • Regulation of L-type voltage-gated calcium channels by epidermal growth factor.

    abstract::GH3 rat pituitary cells have L-type voltage-gated calcium channels, and both the rate of uptake of 45Ca2+ and the concentration of intracellular free calcium ion ([Ca2+]i) are increased by depolarization with high potassium. Cells incubated for several days with 10 nM epidermal growth factor (EGF) responded to depolar...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.133.1.7686480

    authors: Hinkle PM,Nelson EJ,Haymes AA

    更新日期:1993-07-01 00:00:00

  • Effects of thyroid hormone on the insulin receptor in rat liver membranes.

    abstract::Although many studies have investigated the complex interrelationships between thyroid hormone levels and insulin-glucose secretion and action, there is at present a lack of information concerning the effects of various thyroid hormone levels on insulin receptors. In the present study, rat liver membranes were prepare...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-110-6-1922

    authors: DeRuyter H,Burman KD,Wartofsky L,Taylor SI

    更新日期:1982-06-01 00:00:00

  • Identification and characterization of an androgen-responsive gene encoding an aci-reductone dioxygenase-like protein in the rat prostate.

    abstract::The ALP1 [aci-reductone dioxygenase (ARD)-like protein 1] gene was identified in a comprehensive cDNA subtraction aimed at identifying genes regulated by androgens in the rat ventral prostate. ALP1 is homologous to the ARD/ARD' that were discovered in Klebsiella pneumoniae as enzymes that have the same polypeptide seq...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2003-0947

    authors: Oram S,Jiang F,Cai X,Haleem R,Dincer Z,Wang Z

    更新日期:2004-04-01 00:00:00

  • Stimulation of glucose transport by thyroid hormone in ARL 15 cells: increased abundance of glucose transporter protein and messenger ribonucleic acid.

    abstract::We have studied regulation of the glucose transporter by thyroid hormone in ARL 15 cells, a thyroid hormone-responsive cell line derived from rat liver, T3 treatment (5 x 10(-8) M for 48 h) of confluent cell monolayers grown in thyroid hormone-deficient medium increased the rate of uptake of [3H] 2-deoxyglucose by 2.3...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-126-3-1421

    authors: Weinstein SP,Watts J,Graves PN,Haber RS

    更新日期:1990-03-01 00:00:00

  • The presence and ancestral role of gonadotropin-releasing hormone in the reproduction of scleractinian coral, Euphyllia ancora.

    abstract::The objectives of this study were to investigate the presence of immunoreactive GnRH (irGnRH) in scleractinian coral, Euphyllia ancora, study its seasonal variation, and evaluate its biological activity. irGnRH was detected and quantified in coral polyps. The biological activity of coral irGnRH was tested on pituitary...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2005-0584

    authors: Twan WH,Hwang JS,Lee YH,Jeng SR,Yueh WS,Tung YH,Wu HF,Dufour S,Chang CF

    更新日期:2006-01-01 00:00:00

  • Developmental control of plasma leptin and adipose leptin messenger ribonucleic acid in the ovine fetus during late gestation: role of glucocorticoids and thyroid hormones.

    abstract::In developed countries, the increasing incidence of obesity is a serious health problem. Leptin exposure in the perinatal period affects long-term regulation of appetite and energy expenditure, but control of leptin production in utero is unclear. This study investigated perirenal adipose tissue (PAT) and placental le...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2007-0310

    authors: O'Connor DM,Blache D,Hoggard N,Brookes E,Wooding FB,Fowden AL,Forhead AJ

    更新日期:2007-08-01 00:00:00

  • Immediate release of prolactin and biphasic effects on growth hormone release following electrical stimulation of the median eminence.

    abstract::The median eminence (ME) region of the hypothalamus was electrically stimulated through permanently implanted electrodes in 1 unanesthetized sheep. Plasma concentrations of GH and prolactin (PRL) were measured at 10-min intervals before, during and after 30-min periods of electrical stimulation or sham procedures. The...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-97-4-808

    authors: Malven PV

    更新日期:1975-10-01 00:00:00

  • Multiple effects of leucine on glucagon, insulin, and somatostatin secretion from the perfused rat pancreas.

    abstract::The effects of increasing concentrations of leucine (0.2, 2.0, and 15.0 mmol/liter) on glucagon secretion from the perfused rat pancreas were examined at various glucose levels (0, 3.3, or 8.3 mmol/liter) and in the absence or presence of either arginine (5.0 mmol/liter) or glutamine (10.0 mmol/liter). At a low glucos...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-116-3-1168

    authors: Leclercq-Meyer V,Marchand J,Woussen-Colle MC,Giroix MH,Malaisse WJ

    更新日期:1985-03-01 00:00:00

  • Bone Regulation of Insulin Secretion and Glucose Homeostasis.

    abstract::For centuries our image of the skeleton has been one of an inert structure playing a supporting role for muscles and a protective role for inner organs like the brain. Cell biology and physiology modified this view in the 20st century by defining the constant interplay between bone-forming and bone resorbing cells tha...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endocr/bqaa149

    authors: Ducy P

    更新日期:2020-10-01 00:00:00

  • Steroid specificity of the glucocorticoid inhibition of amino acid transport in rat hepatoma cells.

    abstract::Dexamethasone, a synthetic glucocorticoid, inhibits the initial rate of transport of the nonmetabolizable amino acid, alpha-aminoisobutyric acid, in rat hepatoma tissue culture (HTC) cells. To determine whether this inhibition is mediated by the same proximal steps as is the steroidal induction of tyrosine aminotransf...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-109-2-476

    authors: Gelehrter TD,McDonald RA

    更新日期:1981-08-01 00:00:00

  • Fibroblast growth factor 2 reactivates G1 checkpoint in SK-N-MC cells via regulation of p21, inhibitor of differentiation genes (Id1-3), and epithelium-mesenchyme transition-like events.

    abstract::We have recently demonstrated that fibroblast growth factor (FGF)-2 promotes neuroblastoma cell differentiation and overrides their mitogenic response to IGF-I. However, the mechanisms involved are unknown. SK-N-MC cells were cultured with FGF-2 (50 ng/ml) and/or IGF-I (100 ng/ml) up to 48 h. Fluorescence-activated ce...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/en.2008-1797

    authors: Higgins S,Wong SH,Richner M,Rowe CL,Newgreen DF,Werther GA,Russo VC

    更新日期:2009-09-01 00:00:00

  • A stimulatory role of cyclic adenosine 3',5'-monophosphate in follicle-stimulating hormone-activated mitogen-activated protein kinase signaling pathway in rat ovarian granulosa cells.

    abstract::FSH promotes the differentiation of ovarian follicular granulosa cells via a cAMP-dependent mechanism. Based upon the presence of a prominent phospholipid/diolein/Ca2+-independent myelin basic protein kinase activity in soluble extracts of proliferating immature rat granulosa cells, we determine whether this activity ...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo.137.3.8603610

    authors: Das S,Maizels ET,DeManno D,St Clair E,Adam SA,Hunzicker-Dunn M

    更新日期:1996-03-01 00:00:00

  • Effect of food withdrawal and insulin on growth hormone secretion in the guinea pig.

    abstract::The guinea pig is unusual in that its postnatal growth appears to be independent of GH even though its pituitary gland produces a GH molecule. The effects of fasting on the GH secretory pattern and the GH responses to insulin, GH-releasing factor (GRF), and somatostatin (SS) during fasting have now been studied by aut...

    journal_title:Endocrinology

    pub_type: 杂志文章

    doi:10.1210/endo-127-2-716

    authors: Fairhall KM,Gabrielsson BG,Robinson IC

    更新日期:1990-08-01 00:00:00