Gonadal Hormones and Bone.

In both sexes, estrogen is one of the most essential hormones for maintaining bone integrity. Also, especially in men, androgen has beneficial effects on bone independent of estrogen. However, estrogen replacement therapy for postmenopausal women increases the risk of developing breast cancer and endometrial cancer, and androgen replacement therapy for partial androgen deficiency of the aging male increases the risk of developing prostate cancer.

Antitumor agent cabozantinib decreases RANKL expression in osteoblastic cells and inhibits osteoclastogenesis and PTHrP-stimulated bone resorption.

Cabozantinib, an inhibitor of vascular endothelial growth factor and hepatocyte growth factor signaling, decreases bone lesions in patients with prostate cancer. To determine direct effects of cabozantinib on bone, resorption in neonatal mouse bone organ culture and on gene expression, proliferation, and phenotypic markers in osteoblast and osteoclast cell lines were examined. Cabozantinib, 0.

Dentin phosphoprotein binds annexin 2 and is involved in calcium transport in rat kidney ureteric bud cells.

Dentin phosphoprotein (DPP) is the most abundant noncollagenous protein in the dentin, where it plays a major role in the mineralization of dentin. However, we and others have shown that in addition to being present in the dentin, DPP is also present in nonmineralizing tissues like the kidney, lung, and salivary glands, where it conceivably has other functions such as in calcium transport. Because annexins have been implicated as calcium transporters, we examined the relationships between DPP and annexins.

Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project.

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing.

How vitamin D works on bone.

Vitamin D is important for the normal development and maintenance of bone. The elucidation of the vitamin D activation pathway and the cloning of the vitamin D receptor have advanced our understanding of the actions of vitamin D on bone. The preponderance of evidence indicates that 1,25(OH)₂D₃ enhances bone mineralization through its effects to promote calcium and phosphate absorption.

Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model.

We have examined whether Ad.sTβRFc and TAd.sTβRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFβRIIFc), can be developed to treat bone metastasis of prostate cancer.

Regulation of breast cancer-induced bone lesions by β-catenin protein signaling.

Breast cancer patients have an extremely high rate of bone metastases. Morphological analyses of the bones in most of the patients have revealed the mixed bone lesions, comprising both osteolytic and osteoblastic elements. β-Catenin plays a key role in both embryonic skeletogenesis and postnatal bone regeneration.

Sex-specific effects of estrogen and androgen on gene expression in human monocyte-derived osteoclasts.

Estrogen and androgen are both critical for the maintenance of bone, but the target cells, mechanisms, and responses could be sex-specific. To compare sex-specific actions of estrogen and androgen on osteoclasts, human peripheral blood mononuclear precursor cells from adult Caucasian males (n = 3) and females (n = 3) were differentiated into osteoclasts and then treated for 24 h with 17β-estradiol (10 nM) or testosterone (10 nM). Gene expression was studied with a custom designed qPCR-based array containing 94 target genes related to bone and hormone action.

Osteoclastogenic activity and RANKL expression are inhibited in osteoblastic cells expressing constitutively active Gα(12) or constitutively active RhoA.

Gα(12)-RhoA signaling is a parathyroid hormone (PTH)-stimulated pathway that mediates effects in bone and may influence genetic susceptibility to osteoporosis. To further elucidate effects of the pathway in osteoblasts, UMR-106 osteoblastic cells were stably transfected with constitutively active (ca) Gα(12) or caRhoA or dominant negative (dn) RhoA and co-cultured with RAW 264.7 cells to determine effects on hormone-stimulated osteoclastogenesis.

Osteoblast proliferation on hydroxyapatite coated substrates prepared by right angle magnetron sputtering.

The preparation of hydroxyapatite (HA) coatings via a versatile right-angle magnetron sputtering (RAMS) approach for use as a biomaterial has recently been reported. RAMS coatings show some advantages over conventionally sputtered films in that room temperature deposition yields nanocrystalline and nearly stoichiometric HA coatings under appropriate conditions, thereby avoiding the troublesome post deposition annealing treatment. In this article, we present an exploratory study of the biocompatibility of RAMS HA coatings deposited on metallic substrates.

Direct inhibitory and indirect stimulatory effects of RAGE ligand S100 on sRANKL-induced osteoclastogenesis.

Diabetes results in increased fracture risk, and advance glycation endproducts (AGEs) have been implicated in this pathophysiology. S100 proteins are ligands for the receptor of AGEs (RAGE). An intracellular role of the S100 family member S100A4 (Mts1) to suppress mineralization has been described in pre-osteoblastic MC3T3-E1 cells.

Rho GTPase signaling and PTH 3-34, but not PTH 1-34, maintain the actin cytoskeleton and antagonize bisphosphonate effects in mouse osteoblastic MC3T3-E1 cells.

Cytoskeletal elements are critical for cell morphology and signal transduction, and are involved in many cellular processes including motility, intracellular transport, and differentiation. Small GTP-binding proteins (G proteins) of the Ras family, such as RhoA, influence various elements of the cytoskeleton. RhoA stabilizes the actin cytoskeleton and promotes formation of focal adhesions.

The small GTPase RhoA is crucial for MC3T3-E1 osteoblastic cell survival.

Prolongation of cell survival through prevention of apoptosis is considered to be a significant factor leading to anabolic responses in bone. The current studies were carried out to determine the role of the small GTPase, RhoA, in osteoblast apoptosis, since RhoA has been found to be critical for cell survival in other tissues. We investigated the effects of inhibitors and activators of RhoA signaling on osteoblast apoptosis.

Antiresorptive agents and osteoclast apoptosis.

Antiresorptive agents have proven to be effective therapies for the treatment of bone diseases associated with excessive osteoclast activity. Decreased osteoclast formation, inhibition of osteoclast actions, and reduced osteoclast survival represent mechanisms by which antiresorptive agents could act. The goals of this article are to present the evidence that antiresorptive agents can decrease osteoclast survival through apoptosis, to review the mechanisms by which they are thought to activate the apoptotic process, and to consider whether the actions on apoptosis fully account for the antiresorptive effects.

The calcineurin-NFAT pathway and bone: intriguing new findings.

New findings reveal that the calcineurin-NFAT signaling pathway helps to promote osteoblast differentiation. Three recent papers reveal somewhat different mechanisms by which this could occur. In one study, transduction of calcineurin Aalpha increased expression of osteoblast differentiation markers, including Runx-2.

Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts.

Mature bone-resorbing osteoclasts (OCs) mediate excessive bone loss seen in several bone disorders, including osteoporosis. Here, we showed that reveromycin A (RM-A), a small natural product with three carboxylic groups in its structure, induced apoptosis specifically in OCs, but not in OC progenitors, nonfunctional osteoclasts, or osteoblasts. RM-A inhibited protein synthesis in OCs by selectively blocking enzymatic activity of isoleucyl-tRNA synthetase.

Parathyroid hormone stimulates phosphatidylethanolamine hydrolysis by phospholipase D in osteoblastic cells.

Parathyroid hormone (PTH) and phorbol-12,13-dibutyrate (PDBu) stimulate phospholipase D (PLD) activity and PC hydrolysis in UMR-106 osteoblastic cells {Singh, A.T., Kunnel, J.

Receptor activator of NF-kappaB ligand protein expression in UMR-106 cells is differentially regulated by parathyroid hormone and calcitriol.

Expression of the cytokine, receptor activator of NF-kappaB ligand (RANKL), is stimulated by both parathyroid hormone (PTH) and calcitriol in osteoblasts. Most studies have examined the effects on RANKL mRNA, and less information is available on the protein products. We have determined the effects of PTH, the adenylate cyclase stimulator forskolin, and calcitriol, alone and in combination, on endogenous RANKL protein expression in UMR-106 rat osteoblastic osteosarcoma cells by Western blotting and enzyme immunoassay (EIA).

Inhibitory effects of mevastatin and a geranylgeranyl transferase I inhibitor (GGTI-2166) on mononuclear osteoclast formation induced by receptor activator of NF kappa B ligand (RANKL) or tumor necrosis factor-alpha (TNF-alpha).

We have previously reported that the statin mevastatin (compactin) reversibly inhibits the fusion of TRAP-positive mononuclear preosteoclasts (pOCs) into multinucleated osteoclasts and disrupts the actin ring in mature osteoclasts through the inhibition of protein prenylation. Protein geranylgeranylation, specifically, is known to be required for pOC fusion and for the function and survival of mature osteoclasts. However, it has not been determined whether protein geranylgeranylation is involved in early differentiation of osteoclasts (pOC formation).

Rho and Rho kinase are involved in parathyroid hormone-stimulated protein kinase C alpha translocation and IL-6 promoter activity in osteoblastic cells.

Unlabelled: The role of small G-proteins in PTH-stimulated PKC translocation and IL-6 promoter expression in UMR-106 cells was determined. The effects of PTH(1-34) and PTH(3-34) in stimulating PKCalpha translocation and IL-6 were inhibited by agents that interfere with the activity of small G-proteins of the Rho family and with the downstream kinase Rho kinase.

Introduction: Activation of protein kinase C (PKC) is a signaling mechanism by which parathyroid hormone (PTH) modulates interleukin-6 (IL-6) in osteoblasts, leading to osteoclastogenesis and bone resorption.

The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells.

Although best known for its role in T lymphocyte activation, the calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway is also known to be involved in a wide range of other biological responses in a variety of different cell types. Here we have investigated the role of the calcineurin/NFAT signaling pathway in the regulation of osteoclast differentiation. Osteoclasts are bone-resorbing multinucleated cells that are derived from the monocyte/macrophage cell lineage after stimulation with a member of the tumor necrosis factor family of ligands known as receptor activator of nuclear factor-kappaB ligand (RANKL).

IGF-I and MAP kinase involvement in the stimulatory effects of LNCaP prostate cancer cell conditioned media on cell proliferation and protein synthesis in MC3T3-E1 osteoblastic cells.

Bone metastases from prostate cancer cause abnormal new bone formation, however, the factors involved and the pathways leading to the response are incompletely defined. We investigated the mechanisms of osteoblast stimulatory effects of LNCaP prostate carcinoma cell conditioned media (CM). MC3T3-E1 osteoblastic cells were cultured with CM from confluent LNCaP cells.

Role of protein kinase A, phospholipase C and phospholipase D in parathyroid hormone receptor regulation of protein kinase Calpha and interleukin-6 in UMR-106 osteoblastic cells.

Parathyroid hormone (PTH) stimulates both bone formation and resorption by activating diverse osteoblast signalling pathways. Upstream signalling for PTH stimulation of protein kinase C-alpha (PKCalpha) membrane translocation and subsequent expression of the pro-resorptive cytokine interleukin-6 (IL-6) was investigated in UMR-106 osteoblastic cells. PTH 1-34, PTH 3-34, PTHrP and PTH 1-31 stimulated PKCalpha translocation and IL-6 promoter activity.