Tctex-1 augments G protein-coupled receptor-mediated Gs signaling by activating adenylyl cyclase.

Proteins interacting with G protein-coupled receptors (GPCRs) can modulate signal transduction of these receptors. However, the regulatory mechanisms of the interacting proteins are diverse and largely unknown. We have previously shown that Tctex-1 (or DYNLT1) can interact with the parathyroid hormone receptor (PTHR). In the present study, we investigated the role of Tctex-1 in the PTHR signaling and found that Tctex-1 augmented the PTHR-mediated Gs/adenylyl cyclase (AC) pathway by activating AC regardless of the binding to PTHR. Furthermore, Tctex-1 directly bound to AC type 6. These data demonstrate a novel mechanism underlying GPCR/Gs signaling regulated by Tctex-1.

Brief exposure to full length parathyroid hormone-related protein (PTHrP) causes persistent generation of cyclic AMP through an endocytosis-dependent mechanism.

Parathyroid hormone (PTH)-related protein (PTHrP) (gene name Pthlh) was discovered as the factor responsible for the humoral hypercalcemia of malignancy. It shares such sequence similarity with PTH in the amino-terminal region that the two are equally able to act through a single G protein-coupled receptor, PTH1R. A number of biological activities are ascribed to domains of PTHrP beyond the amino-terminal domain. PTH functions as a circulating hormone, but PTHrP is generated locally in many tissues including bone, where it acts as a paracrine factor on osteoblasts and osteocytes. The present study compares how PTH and PTHrP influence cyclic AMP (cAMP) formation through adenylyl cyclase, the first event in cell activation through PTH1R. Brief exposure to full length PTHrP(1-141) in several osteoblastic cell culture systems was followed by sustained adenylyl cyclase activity for more than an hour after ligand washout. This effect was dose-dependent and was not found with shorter PTHrP or PTH peptides even though they were fully able to activate adenylyl cyclase with acute treatment. The persistent activation response to PTHrP(1-141) was seen also with later events in the cAMP/PKA pathway, including persistent activation of CRE-luciferase and sustained regulation of several CREB-responsive mRNAs, up to 24 h after the initial exposure. Pharmacologic blockade of endocytosis prevented the persistent activation of cAMP and gene responses. We conclude that full length PTHrP, the likely local physiological effector in bone, differs in intracellular action to PTH by undergoing endosomal translocation to induce a prolonged adenylyl cyclase activation in its target cells.

PTHR1 May Be Involved in Progression of Osteosarcoma by Regulating miR-124-3p-AR-Tgfb1i1, miR-27a-3p-PPARG-Abca1, and miR-103/590-3p-AXIN2 Axes.

Our previous study has indicated that the parathyroid hormone type 1 receptor (PTHR1) may play important roles in development and progression of osteosarcoma (OS) by regulating Wnt, angiogenesis, and inflammation pathway genes. The goal of this study was to further illuminate the roles of PTHR1 in OS by investigating upstream regulation mechanisms (including microRNA [miRNA] and transcription factors [TFs]) of crucial genes. The microarray dataset GSE46861 was downloaded from the Gene Expression Omnibus database, in which six tumors with short hairpin RNA (shRNA) PTHR1 knockdown (PTHR1.358) and six tumors with shRNA control knockdown (Ren.1309) were collected from mice. Differentially expressed genes (DEGs) between PTHR1.358 and Ren.1309 were identified using the linear models for microarray data (LIMMA) method, and then the miRNA-TF-mRNA regulatory network was constructed using data from corresponding databases, followed by module analysis, to screen crucial regulatory relationships. OS-related human miRNAs were extracted from the curated Osteosarcoma Database. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. As a result, the miRNA-TF-mRNA regulatory network, including 1049 nodes (516 miRNA, 25 TFs, and 508 DEGs) and 15942 edges (interaction relationships, such as Pparg-Abca1 and miR-590-3p-AXIN2), was constructed, from which three significant modules were extracted and modules 2 and 3 contained interactions between miRNAs/TFs and DEGs such as miR-103-3p-AXIN2, miR-124-3p-AR-Tgfb1i1, and miR-27a-3p-PPARG-Abca1. miR-27a-3p was a known miRNA associated with OS. Abca1, AR, and miR-124-3p were hub genes in the miRNA-TF-mRNA network. Tgfb1i1 was involved in cell proliferation, Abca1 participated in the cholesterol metabolic process, and AXIN2 was associated with the canonical Wnt signaling pathway. Furthermore, we also confirmed upregulation of miR-590-3p and downregulation of AXIN2 in the mouse OS cell line K7M2-WT transfected with PTHR1 shRNA. In conclusion, PTHR1 may play important roles in progression of OS by activating miR-124-3p-AR-Tgfb1i1, miR-27a-3p-PPARG-Abca1, and miR-103/590-3p-AXIN2 axes.

PTH1R signalling regulates the mechanotransduction process of cementoblasts under cyclic tensile stress.

Objective: To investigate the regulatory role of type I parathyroid hormone receptor (PTH1R) signalling in the mechanotransduction process of cementoblasts under cyclic tensile stress (CTS). Materials and methods: Immortalized cementoblast cell line OCCM-30 were employed and subjected to cyclic tensile strain applied by a four-point bending system. The expression of PTHrP and PTH1R, as well as cementoblastic transcription factor Runx-2, Osterix, and extracellular matrix protein COL-1 and OPN were assessed by quantitative real-time polymerase chain reaction and western blot analysis. PTH1R expression was knocked down by siPTH1R transfection, and the alteration of cementoblastic biomarkers expression was examined to evaluate the function of PTH1R. Furthermore, to investigate possible downstream molecules, expression of signal molecule ERK1/2 with or without siPTH1R transfection, and the effect of ERK inhibitor PD98059 on the expression of cementoblastic biomarkers was also examined. Results: Cyclic tensile strain elevated the expression of PTHrP and PTH1R, as well as cementoblastic biomarkers Runx-2, Osterix, COL-1, and OPN in a time-dependent manner, which was inhibited by siPTH1R transfection. The expression of phosphorylated ERK1/2 was upregulated time-dependently under cyclic stretch, which was also inhibited by siPTH1R transfection, and pretreatment of p-ERK1/2 inhibitor PD98059 undermined the increase of Runx-2, Osterix, COL-1, and OPN prominently. Conclusion: The findings of the present study indicate that PTH1R signalling plays a regulatory role in the CTS induced cementoblastic differentiation in mature cementoblasts, and ERK1/2 is essentially involved as a downstream intracellular signal molecule in this mechanotransduction process.

PTH and PTHR1 in osteocytes. New insights into old partners.

Parathyroid hormone receptors are present in bone cells and play a crucial role in the maintenance of skeletal integrity, bone homeostasis and regulation of calcium and phosphate metabolism. Although the function of these receptors has long being recognized in the cells of the osteoblastic lineage regulating directly osteoblast differentiation and function and indirectly osteoclastogenesis, recent findings demonstrate their functional presence in osteocytes participating in the co-ordination of bone remodelling. In this review we focus on the key roles of these receptors in osteoblasts and osteocytes, combining what is known and what is new regarding these interesting pleiotropic hormone receptors.

Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism.

Parathyroid hormone (PTH)-related peptide (PTHrP) controls the pace of pre- and post-natal growth plate development by activating the PTH1R in chondrocytes, while PTH maintains mineral and skeletal homeostasis by modulating calciotropic activities in kidneys, gut, and bone. The extracellular calcium-sensing receptor (CaSR) is a member of family C, G protein-coupled receptor, which regulates mineral and skeletal homeostasis by controlling PTH secretion in parathyroid glands and Ca(2+) excretion in kidneys. Recent studies showed the expression of CaSR in chondrocytes, osteoblasts, and osteoclasts and confirmed its non-redundant roles in modulating the recruitment, proliferation, survival, and differentiation of the cells. This review emphasizes the actions of CaSR and PTH1R signaling responses in cartilage and bone and discusses how these two signaling cascades interact to control growth plate development and maintain skeletal metabolism in physiological and pathological conditions. Lastly, novel therapeutic regimens that exploit interrelationship between the CaSR and PTH1R are proposed to produce more robust osteoanabolism.

Informatic deconvolution of biased GPCR signaling mechanisms from in vivo pharmacological experimentation.

Ligands possessing different physico-chemical structures productively interact with G protein-coupled receptors generating distinct downstream signaling events due to their abilities to activate/select idiosyncratic receptor entities ('receptorsomes') from the full spectrum of potential receptor partners. We have employed multiple novel informatic approaches to identify and characterize the in vivo transcriptomic signature of an arrestin-signaling biased ligand, [D-Trp(12),Tyr(34)]-bPTH(7-34), acting at the parathyroid hormone type 1 receptor (PTH1R), across six different murine tissues after chronic drug exposure. We are able to demonstrate that [D-Trp(12),Tyr(34)]-bPTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated, in an arrestin signaling-dependent manner, across more tissues than that of the pluripotent endogenous PTH1R ligand, hPTH(1-34). This arrestin-focused response signature is strongly linked with the transcriptional regulation of cell growth and development. Our informatic deconvolution of a conserved arrestin-dependent transcriptomic signature from wild type mice demonstrates a conceptual framework within which the in vivo outcomes of biased receptor signaling may be further investigated or predicted.

PTH receptor-1 signalling-mechanistic insights and therapeutic prospects.

Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR) that regulates skeletal development, bone turnover and mineral ion homeostasis. PTHR1 transduces stimuli from PTH and PTHrP into the interior of target cells to promote diverse biochemical responses. Evaluation of the signalling properties of structurally modified PTHR1 ligands has helped to elucidate determinants of receptor function and mechanisms of downstream cellular and physiological responses. Analysis of PTHR1 responses induced by structurally modified ligands suggests that PTHR1 can continue to signal through a G-protein-mediated pathway within endosomes. Such findings challenge the longstanding paradigm in GPCR biology that the receptor is transiently activated at the cell membrane, followed by rapid deactivation and receptor internalization. Evaluation of structurally modified PTHR1 ligands has further led to the identification of ligand analogues that differ from PTH or PTHrP in the type, strength and duration of responses induced at the receptor, cellular and organism levels. These modified ligands, and the biochemical principles revealed through their use, might facilitate an improved understanding of PTHR1 function in vivo and enable the treatment of disorders resulting from defects in PTHR1 signalling. This Review discusses current understanding of PTHR1 modes of action and how these findings might be applied in future therapeutic agents.

Effect of parathyroid hormone on early chondrogenic differentiation from mesenchymal stem cells.

BACKGROUND: Treatment of articular cartilage injuries remains a difficult challenge due to the limited capacity for intrinsic repair. Mesenchymal stem cells (MSCs) can differentiate into chondrocytes under certain culture conditions. This study focused on the modulatory effects of parathyroid hormone (PTH) on chondrogenic differentiation from MSCs. METHODS: MSCs were treated with various concentrations of PTH under chondrogenic pellet culture condition. RNA was isolated for real-time polymerase chain reaction (PCR) and gene expressions of collagen type II α1 chain (Col2a1), collagen type X α1 chain, collagen type I α1 chain, SRY-box9 (Sox9), and type 1 PTH/PTHrP receptor (PTH1R) were examined. Chondrogenic differentiation was also evaluated by histological findings. RESULTS: PTH had opposite effects on chondrogenesis, depending on the concentration. A low to moderate concentration of PTH promoted chondrogenic differentiation of MSCs with increased expression of Sox9, Col2a1, and PTH1R, whereas chondrogenesis of MSCs was inhibited rather than stimulated with a higher concentration of PTH. CONCLUSION: This study provides insights into the modulatory effect of PTH on chondrogenic differentiation from MSCs and the therapeutic potential for cartilage regeneration. Based on clinical experience regarding the efficacy and safety of PTH for bone metabolism, PTH may also be useful clinically for cartilage repair.

Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase.

The PTH receptor is to our knowledge one of the first G protein-coupled receptor (GPCR) found to sustain cAMP signaling after internalization of the ligand-receptor complex in endosomes. This unexpected model is adding a new dimension on how we think about GPCR signaling, but its mechanism is incompletely understood. We report here that endosomal acidification mediated by the PKA action on the v-ATPase provides a negative feedback mechanism by which endosomal receptor signaling is turned off.

[Role for PTHrP in bone and cartilage metabolism].

PTH-related peptide (PTHrP) is a widely distributed cytokine, which shares the cognate receptor PTHR1 with PTH. Originally identified as a causal factor of humoral hypercalcemia of malignancy twenty years ago, PTHrP is now recognized as a critical physiological regulator of various biological processes, including bone and cartilage metabolism.

Roles of parathyroid hormone (PTH) receptor and reactive oxygen species in hyperlipidemia-induced PTH resistance in preosteoblasts.

Bioactive lipids initiate inflammatory reactions leading to pathogenesis of atherosclerosis. Evidence shows that they also contribute to bone loss by inhibiting parathyroid hormone receptor (PTH1R) expression and differentiation of osteoblasts. We previously demonstrated that bone anabolic effects of PTH(1-34) are blunted in hyperlipidemic mice and that these PTH effects are restored by antioxidants. However, it is not clear which osteoblastic cell developmental stage is targeted by bioactive lipids. To investigate the effects of hyperlipidemia at the cellular level, hyperlipidemic Ldlr(-/-) mice were bred with Col3.6GFPtpz mice, in which preosteoblasts/osteoblasts carry a topaz fluorescent label, and with Col2.3GFPcyan mice, in which more mature osteoblasts/osteocytes carry a cyan fluorescent label. Histological analyses of trabecular bone surfaces in femoral as well as calvarial bones showed that intermittent PTH(1-34) increased fluorescence intensity in WT-Tpz mice, but not in Tpz-Ldlr(-/-) mice. In contrast, PTH(1-34) did not alter fluorescence intensity in femoral cortical envelopes of either WT-Cyan or Ldlr(-/-)-Cyan mice. To test the mechanism of PTH1R downregulation, preosteoblastic MC3T3-E1 cells were treated with bioactive lipids and the antioxidant Trolox. Results showed that inhibitory effects of PTH1R levels by bioactive lipids were rescued by pretreatment with Trolox. The inhibitory effects on expression of PTH1R as well as on PTH-induced osteoblastic genes were mimicked by xanthine/xanthine oxidase, a known generator of reactive oxygen species. These findings suggest an important role of the preosteoblastic development stage as the target and downregulation of PTH receptor expression mediated by intracellular oxidant stress as a mechanism in hyperlipidemia-induced PTH resistance.

PTHrP is endogenous relaxant for spontaneous smooth muscle contraction in urinary bladder of female rat.

Acute bladder distension causes various morphologic and functional changes, in part through altered gene expression. We aimed to investigate the physiologic role of PTHrP, which is up-regulated in an acute bladder distension model in female rats. In the control Empty group, bladders were kept empty for 6 hours, and in the Distension group, bladders were kept distended for 3 hours after an artificial storing-voiding cycle for 3 hours. In the Distention group bladder, up-regulation of transcripts was noted for 3 genes reported to be up-regulated by stretch in the cultured bladder smooth muscle cells in vitro. Further transcriptome analysis by microarray identified PTHrP as the 22nd highest gene up-regulated in Distension group bladder, among more than 27,000 genes. Localization of PTHrP and its functional receptor, PTH/PTHrP receptor 1 (PTH1R), were analyzed in the untreated rat bladders and cultured bladder cells using real-time RT-PCR and immunoblotting, which revealed that PTH1R and PTHrP were more predominantly expressed in smooth muscle than in urothelium. Exogenous PTHrP peptide (1-34) increased intracellular cAMP level in cultured bladder smooth muscle cells. In organ bath study using bladder strips, the PTHrP peptide caused a marked reduction in the amplitude of spontaneous contraction but caused only modest suppression for carbachol-induced contraction. In in vivo functional study by cystometrogram, the PTHrP peptide decreased voiding pressure and increased bladder compliance. Thus, PTHrP is a potent endogenous relaxant of bladder contraction, and autocrine or paracrine mechanism of the PTHrP-PTH1R axis is a physiologically relevant pathway functioning in the bladder.

Activation of a non-cAMP/PKA signaling pathway downstream of the PTH/PTHrP receptor is essential for a sustained hypophosphatemic response to PTH infusion in male mice.

PTH increases urinary Pi excretion by reducing expression of two renal cotransporters [NaPi-IIa (Npt2a) and NaPi-IIc (Npt2c)]. In contrast to acute transporter regulation that is cAMP/protein kinase A dependent, long-term effects require phospholipase C (PLC) signaling by the PTH/PTHrP receptor (PPR). To determine whether the latter pathway regulates Pi through Npt2a and/or Npt2c, wild-type mice (Wt) and animals expressing a mutant PPR incapable of PLC activation (DD) were tested in the absence of one (Npt2a(-/-) or Npt2c(-/-)) or both phosphate transporters (2a/2c-dko). PTH infusion for 8 days caused a rapid and persistent decrease in serum Pi in Wt mice, whereas serum Pi in DD mice fell only transiently for the first 2 days. Consistent with these findings, fractional Pi excretion index was increased initially in both animals, but this increase persisted only when the PPR Wt was present. The hypophosphatemic response to PTH infusion was impaired only slightly in PPR Wt/Npt2c(-/-) or DD/Npt2c(-/-) mice. Despite lower baselines, PTH infusion in PPR Wt/Npt2a(-/-) mice decreased serum Pi further, an effect that was attenuated in DD/Npt2a(-/-) mice. Continuous PTH had no effect on serum Pi in 2a/2c-dko mice. PTH administration increased serum 1,25 dihydroxyvitamin D3 levels in Wt and DD mice and increased levels above the elevated baseline with ablation of either but not of both transporters. Continuous PTH elevated serum fibroblast growth factor 23 and blood Ca(2+) equivalently in all groups of mice. Our data indicate that PLC signaling at the PPR contributes to the long-term effect of PTH on Pi homeostasis but not to the regulation of 1,25 dihydroxyvitamin D3, fibroblast growth factor 23, or blood Ca(2+).

Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH.

Agonist-induced phosphorylation of the parathyroid hormone (PTH) receptor 1 (PTHR1) regulates receptor signaling in vitro, but the role of this phosphorylation in vivo is uncertain. We investigated this role by injecting "knock-in" mice expressing a phosphorylation-deficient (PD) PTHR1 with PTH ligands and assessing acute biologic responses. Following injection with PTH (1-34), or with a unique, long-acting PTH analog, PD mice, compared with WT mice, exhibited enhanced increases in cAMP levels in the blood, as well as enhanced cAMP production and gene expression responses in bone and kidney tissue. Surprisingly, however, the hallmark hypercalcemic and hypophosphatemic responses were markedly absent in the PD mice, such that paradoxical hypocalcemic and hyperphosphatemic responses were observed, quite strikingly with the long-acting PTH analog. Spot urine analyses revealed a marked defect in the capacity of the PD mice to excrete phosphate, as well as cAMP, into the urine in response to PTH injection. This defect in renal excretion was associated with a severe, PTH-induced impairment in glomerular filtration, as assessed by the rate of FITC-inulin clearance from the blood, which, in turn, was explainable by an overly exuberant systemic hypotensive response. The overall findings demonstrate the importance in vivo of PTH-induced phosphorylation of the PTHR1 in regulating acute ligand responses, and they serve to focus attention on mechanisms that underlie the acute calcemic response to PTH and factors, such as blood phosphate levels, that influence it.

The guanine nucleotide exchange factor Vav2 is a negative regulator of parathyroid hormone receptor/Gq signaling.

The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor (GPCR) that mediates the endocrine and paracrine effects of parathyroid hormone and related peptides through the activation of phospholipase Cß-, adenylyl cyclase-, mitogen-activated protein kinase-, and ß-arrestin-initiated signaling pathways. It is currently not clear how specificity among these downstream signaling pathways is achieved. A possible mechanism involves adaptor proteins that affect receptor/effector coupling. In a proteomic screen with the PTHR C terminus, we identified vav2, a guanine nucleotide exchange factor (GEF) for Rho GTPases, as a PTHR-interacting protein. The core domains of vav2 bound to the intracellular domains of the PTHR independent of receptor activation. In addition, vav2 specifically interacted with activated Gα(q) but not with Gα(s) subunits, and it competed with PTHR for coupling to Gα(q). Consistent with its specific interaction with Gα(q), vav2 impaired G(q)-mediated inositol phosphate generation but not G(s)-mediated cAMP generation. This inhibition of G(q) signaling was specific for PTHR signaling, compared with other G(q)-coupled GPCRs. Moreover, the benefit for PTHR-mediated inositol phosphate generation in the absence of vav2 required the ezrin binding domain of Na(+)/H(+)-exchanger regulatory factor 1. Our results show that a RhoA GEF can specifically interact with a GPCR and modulate its G protein signaling specificity.

[Anabolic action of PTH under the loading/unloading condition].

Parathyroid hormone (PTH) is available for the treatment of osteoporosis in Japan. PTH is administered subcutaneously daily or weekly. According to the results of animal experiments, the anabolic action of PTH on bone depends on dosage, condition of loading, and region of bone. Administration of PTH preserved trabecular bone formation rate reduced by immobilization or unloading at the same level of that under the normal mobilization or loading condition, but at low dose did not preserve periosteal bone formation rate reduced by unloading. PTH at high dose (40µg/kg BW) completely preserved trabecular bone volume reduced by immobilization in mice. Thus, we consider that PTH could be clinically effective for immobilization- and/or unloading-induced bone loss.

Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells.

Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.

The parathyroid hormone receptorsome and the potential for therapeutic intervention.

The parathyroid hormone 1 receptor (PTH1R) is activated by parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP), hormones that mediate mineral ion homeostasis and tissue development, respectively. These diverse actions mediated by one receptor are likely due to the formation of cell-specific receptorsome complexes with cytosolic constituents. Through the second and third intracellular loops, the PTH1R couples to several G protein subclasses, including Gs, Gq/11, Gi/o and G12/13, resulting in the activation of many pathways. The PTH1R carboxy-terminal tail directs interactions with a plethora of binding partners. The WD1 and WD7 repeats of the G protein ß subunit directly bind to a novel interaction domain located near the amino-terminal end of the PTH1R carboxy-terminal tail. This Gßγ binding site likely contributes to the promiscuous G protein coupling displayed by the PTH1R. Partially overlapping this site is an EF-hand binding domain that directs interactions with calpain, a calcium-activated protease, and calmodulin, a ubiquitous calcium sensor. A lysine-arginine-lysine motif located on the juxtamembrane region of the carboxy-terminal tail mediates interactions with ezrin, an actin-membrane cross-linking protein. The C-terminus of the PTH1R binds to the sodium-hydrogen regulatory factors (NHERFs) via a PDZ domain-mediated interaction, an association that influences signaling and membrane anchoring. Through direct interactions with ezrin and NHERF-1, a PTH1R receptorsome complex exists on apical membranes of the proximal tubule, an assembly that directs PTH-mediated regulation of phosphate transport. Targeting the PTH1R receptorsome will likely enhance therapies directed towards the treatment of osteoporosis and enhancing the hematopoietic stem cell niche.

[Tooth and bone research using genetically modified mice].

Teeth and bone are both hard tissues and composed of hydroxyapatite. Tooth development initiates with the invasination of oral epithelium, followed by aggregation of supporting ectomesenchymal cells. From mouse study, numbers of molecules have been discovered to relate tooth development. These discoveries have helped to clarify the responsible genes of human genetic disorders with abnormal tooth number and structure. During tooth development, teeth erupt into the outer environment, oral cavity. From this point, teeth are completely different from bone which is always covered by soft tissues. Tooth eruption is composed of two different processes, that is, eruption pathway formation and vertical tooth movement. In this review, mutant mice with abnormal tooth development and eruption are introduced, and molecular mechanism required for this process is discussed.