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• W1986179699 abstract "Reduced bone mass is a common complication in chronic inflammatory diseases, although the mechanisms are not completely understood. The PHEX gene encodes a zinc endopeptidase expressed in osteoblasts and contributes to bone mineralization. The aim of this study was to determine the molecular mechanism involved in TNF-mediated down-regulation of Phex gene transcription. We demonstrate down-regulation of the Phex gene in two models of colitis: naive T-cell transfer and in gnotobiotic IL-10−/− mice. In vitro, TNF decreased expression of Phex in UMR106 cells and did not require de novo synthesis of a transrepressor. Transfecting UMR-106 cells with a series of deletion constructs of the proximal Phex promoter identified a region located within −74 nucleotides containing NF-κB and AP-1 binding sites. After TNF treatment, the RelA/p50 NF-κB complex interacted with two cis-elements at positions −70/−66 and −29/−25 nucleotides in the proximal Phex promoter. Inhibition of NF-κB signaling increased the basal level of Phex transcription and abrogated the effects of TNF, whereas overexpression of RelA mimicked the effect of TNF. We identified poly(ADP-ribose) polymerase 1 (PARP-1) binding immediately upstream of the NF-κB sites and showed that TNF induced poly(ADP-ribosyl)ation of RelA when bound to the Phex promoter. TNF-mediated Phex down-regulation was completely abrogated in vitro by PARP-1 inhibitor and overexpression of poly(ADP-ribose) glucohydrolase (PARG) and in vivo in PARP-1−/− mice. Our results suggest that NF-κB signaling and PARP-1 enzymatic activity cooperatively contribute to the constitutive and inducible suppression of Phex. The described phenomenon likely contributes to the loss of bone mass density in chronic inflammatory diseases, such as inflammatory bowel disease. Reduced bone mass is a common complication in chronic inflammatory diseases, although the mechanisms are not completely understood. The PHEX gene encodes a zinc endopeptidase expressed in osteoblasts and contributes to bone mineralization. The aim of this study was to determine the molecular mechanism involved in TNF-mediated down-regulation of Phex gene transcription. We demonstrate down-regulation of the Phex gene in two models of colitis: naive T-cell transfer and in gnotobiotic IL-10−/− mice. In vitro, TNF decreased expression of Phex in UMR106 cells and did not require de novo synthesis of a transrepressor. Transfecting UMR-106 cells with a series of deletion constructs of the proximal Phex promoter identified a region located within −74 nucleotides containing NF-κB and AP-1 binding sites. After TNF treatment, the RelA/p50 NF-κB complex interacted with two cis-elements at positions −70/−66 and −29/−25 nucleotides in the proximal Phex promoter. Inhibition of NF-κB signaling increased the basal level of Phex transcription and abrogated the effects of TNF, whereas overexpression of RelA mimicked the effect of TNF. We identified poly(ADP-ribose) polymerase 1 (PARP-1) binding immediately upstream of the NF-κB sites and showed that TNF induced poly(ADP-ribosyl)ation of RelA when bound to the Phex promoter. TNF-mediated Phex down-regulation was completely abrogated in vitro by PARP-1 inhibitor and overexpression of poly(ADP-ribose) glucohydrolase (PARG) and in vivo in PARP-1−/− mice. Our results suggest that NF-κB signaling and PARP-1 enzymatic activity cooperatively contribute to the constitutive and inducible suppression of Phex. The described phenomenon likely contributes to the loss of bone mass density in chronic inflammatory diseases, such as inflammatory bowel disease. IntroductionBones have several physiological functions including maintaining organism structure, serving as a hematopoietic niche, calcium and inorganic phosphate reservoir, and regulating and feeding back to other organs via hormone release. To balance both normal serum mineral concentrations and bone mineral density, bones have a dynamic homeostasis that involve bone-forming osteoblasts and bone-resorbing osteoclasts. This balance is influenced by hormones, neurotransmitters, and cytokines that act directly on osteoblasts and osteoclasts to affect mineral deposition and release (1Caetano-Lopes J. Canhão H. Fonseca J.E. Autoimmun. Rev. 2009; 8: 250-255Crossref PubMed Scopus (113) Google Scholar).Although normal bone structure is the result of the balance of these two opposite processes, certain genetic disorders can skew this balance leading to low bone mineralization. In vitamin D-resistant, X-linked hypophosphatemic rickets, an inactivating mutation of PHEX 3The abbreviations used are: PHEXphosphate-regulating gene with homologies to endopeptidases on the X chromosomeIBDinflammatory bowel diseasePARP-1poly(ADP-ribose) polymerase 1PARGpoly(ADP-ribose) glycohydrolaseDAPADNA affinity precipitation assayRNAP IIRNA polymerase IITSStranscriptional start site3-AB3-aminobenzamidecLβLclasto-lactacystin-β-lactonentnucleotide(s)SPFspecific pathogen freeNPnuclear proteinCHXcycloheximideICAM-1intercellular adhesion molecule 1PMPparamagnetic particlesKOknock-out. (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) leads to hypophosphatemia, aberrant vitamin D levels, high serum alkaline phosphatase, and osteomalacia (2Francis F. Hennig S. Korn B. Reinhardt R. de Jong P. Poustka A. Lehrach H. Rowe P.S. Goulding J.N. Summerfield T. Mountford R. Read A.P. Popowska E. Pronicka E. Davies K.E. O'Riordan J.L. Econs M.J. Nesbitt T. Drezner M.K. Oudet C. Pannetier S. Hanauer A. Strom T.M. Meindl A. Lorenz B. Cagnoli B. Mohnike K.L. Murken J. Meitinger T. Nat. Genet. 1995; 11: 130-136Crossref PubMed Scopus (957) Google Scholar, 3Strom T.M. Francis F. Lorenz B. Böddrich A. Econs M.J. Lehrach H. Meitinger T. Hum. Mol. Genet. 1997; 6: 165-171Crossref PubMed Scopus (174) Google Scholar). Although the Phex gene encodes a membrane-bound, zinc metallopeptidase expressed only in osteoblasts and odontoblasts, the effects of its mutation lead to phosphate wasting in the kidney by decreasing the expression and activity of the Na+/Pi cotransporter, NaPi-IIa (NPT2; SLC24A1) in proximal convoluted tubules (4Collins J.F. Scheving L.A. Ghishan F.K. Am. J. Physiol. Renal Physiol. 1995; 269: F439-F448Crossref PubMed Google Scholar, 5Tenenhouse H.S. Annu. Rev. Nutr. 2005; 25: 197-214Crossref PubMed Scopus (146) Google Scholar). Phex inactivation was postulated to indirectly affect the kidney through bone-released, phosphaturic factors known as phosphatonins. Fibroblast growth factor 23 (FGF23) was one of the leading phosphatonin candidates due to its potent negative effects on renal phosphate reabsorption and its highly elevated expression in X-linked hypophosphatemic ricket patients (6Kiela P.R. Ghishan F.K. Lab. Invest. 2009; 89: 7-14Crossref PubMed Scopus (51) Google Scholar). Although initial studies seemed to confirm this mechanism (7Bowe A.E. Finnegan R. Jan de Beur S.M. Cho J. Levine M.A. Kumar R. Schiavi S.C. Biochem. Biophys. Res. Commun. 2001; 284: 977-981Crossref PubMed Scopus (294) Google Scholar), it was later shown that Phex mutations lead to increased FGF23 expression rather than processing (8Liu S. Guo R. Simpson L.G. Xiao Z.S. Burnham C.E. Quarles L.D. J. Biol. Chem. 2003; 278: 37419-37426Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar), and that FGF23 is cleaved by subtilisin-like proprotein convertases and not PHEX (9Benet-Pagès A. Lorenz-Depiereux B. Zischka H. White K.E. Econs M.J. Strom T.M. Bone. 2004; 35: 455-462Crossref PubMed Scopus (208) Google Scholar).In addition to the renal abnormalities in X-linked hypophosphatemic rickets, PHEX inactivation also leads to osteoblast mineralization deficits. This is exemplified by the inability of immortalized osteoblasts from Phex-deficient Hyp mice to mineralize in vitro (10Xiao Z.S. Crenshaw M. Guo R. Nesbitt T. Drezner M.K. Quarles L.D. Am. J. Physiol. Endocrinol. Metab. 1998; 275: E700-E708Crossref PubMed Google Scholar). Although the target(s) of PHEX proteolytic activity remains uncertain, PHEX protein may influence bone metabolism by binding and stabilizing matrix extracellular phosphoglycoprotein, dentine matrix protein 1 (DMP1) (11Martin A. David V. Laurence J.S. Schwarz P.M. Lafer E.M. Hedge A.M. Rowe P.S. Endocrinology. 2008; 149: 1757-1772Crossref PubMed Scopus (138) Google Scholar), and osteopontin (12Addison W. Masica D. Gray J. McKee M.D. J. Bone Miner. Res. 2010; 25: 695-705Crossref PubMed Scopus (15) Google Scholar). Specifically, when PHEX binds to these substrates, it prevents their cleavage and release of a small, acidic protease-resistant ASARM peptide (acidic serine-aspartate-rich matrix extracellular phosphoglycoprotein-associated motif). These ASARM peptides have been shown to inhibit mineralization in vivo and in vitro, and most likely function by directly binding to hydroxyapatite crystals and by decreasing the expression of Phex (13Addison W.N. Nakano Y. Loisel T. Crine P. McKee M.D. J. Bone Miner Res. 2008; 23: 1638-1649Crossref PubMed Scopus (158) Google Scholar).PHEX itself is regulated by several hormones and cytokines important for skeletal homeostasis. Phex is up-regulated after treatment with insulin-like growth factor 1, growth hormone (14Zoidis E. Gosteli-Peter M. Ghirlanda-Keller C. Meinel L. Zapf J. Schmid C. Eur. J. Endocrinol. 2002; 146: 97-105Crossref PubMed Scopus (43) Google Scholar), and glucocorticoids (15Hines E.R. Collins J.F. Jones M.D. Serey S.H. Ghishan F.K. Am. J. Physiol. Renal Physiol. 2002; 283: F356-F363Crossref PubMed Scopus (18) Google Scholar). Alternatively, Phex was found to be down-regulated by parathyroid hormone (16Alos N. Ecarot B. Bone. 2005; 37: 589-598Crossref PubMed Scopus (16) Google Scholar), parathyroid hormone-related peptide (17Vargas M.A. St-Louis M. Desgroseillers L. Charli J.L. Boileau G. Endocrinology. 2003; 144: 4876-4885Crossref PubMed Scopus (16) Google Scholar), and vitamin D (18Hines E.R. Kolek O.I. Jones M.D. Serey S.H. Sirjani N.B. Kiela P.R. Jurutka P.W. Haussler M.R. Collins J.F. Ghishan F.K. J. Biol. Chem. 2004; 279: 46406-46414Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar).We have shown that the proinflammatory cytokine TNF decreases Phex expression in vivo and in vitro (19Uno J.K. Kolek O.I. Hines E.R. Xu H. Timmermann B.N. Kiela P.R. Ghishan F.K. Gastroenterology. 2006; 131: 497-509Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar), an observation with significant pathophysiological implications. During chronic inflammation such as in inflammatory bowel diseases (IBD), circulating and/or infiltrating lymphocytes and other mononuclear cells produce cytokines that can influence bone metabolism by altering the balance of bone mineral deposition and resorption. Decreased bone mineral density is a common outcome of IBD. Indeed, 31 to 59% of adult IBD patients are classified as osteopenic, whereas 5 to 41% are actually diagnosed with osteoporosis, although rates of up to 70% of adult and pediatric IBD patients with low bone mineral density have been reported (20Rodríguez-Bores L. Barahona-Garrido J. Yamamoto-Furusho J.K. World J. Gastroenterol. 2007; 13: 6156-6165Crossref PubMed Scopus (60) Google Scholar). In our earlier study (19Uno J.K. Kolek O.I. Hines E.R. Xu H. Timmermann B.N. Kiela P.R. Ghishan F.K. Gastroenterology. 2006; 131: 497-509Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar), we showed that TNF treatment and chemically induced colitis decrease Phex mRNA expression via a transcriptional mechanism, and that the polyadenine (poly(A)) region located −116 to −110 bp upstream of the transcriptional start site was necessary for the TNF-mediated inhibition. This decrease in Phex expression correlated with decreased mineral deposition in osteoblast-like UMR-106 cells.In the present work, we extend our previous observations to demonstrate the down-regulation of Phex in two more representative models of human IBD: microflora-induced colitis in gnotobiotic IL-10−/− mice and adoptive CD4+CD45RBhigh T-cell transfer into Rag2−/− recipients. Phex gene promoter analysis showed that the polyadenine (poly(A)) region in the murine Phex promoter constitutively binds PARP-1, whereas TNF induces binding of the NF-κB complex proximally to this element. RelA is then PARylated to increase its activity as a transrepressor. PARP-1 activity was indispensable for the effects of TNF as demonstrated by a blunted response to the cytokine in the presence of a PARP-1 inhibitor or overexpressed poly(ADP-ribose) glycohydrolase (PARG), and by a complete abrogation of the response to TNF in PARP-1 knock-out mice.DISCUSSIONThe skeletal and immune systems share numerous key players and regulatory mechanisms, an overlap that gave rise to the emerging field of osteoimmunology. A detailed understanding of the pathogenesis of bone destruction as a result of the interaction of immune cells and inflammatory mediators with bone cells is critical in designing novel strategies for the treatment of several disorders. These include rheumatoid arthritis, periodontal disease, Paget disease, osteoarthritis, multiple myeloma, metastatic bone tumors, and chronic inflammation-associated loss of bone mineral density. The latter is increasingly more recognized by the gastroenterology community due to a significant association of chronic IBD with osteopenia and osteoporosis (25Tilg H. Moschen A.R. Kaser A. Pines A. Dotan I. Gut. 2008; 57: 684-694Crossref PubMed Scopus (209) Google Scholar). Bone loss in chronic inflammation is believed to be at least in part mediated by proinflammatory cytokines such as TNF, IL-1β, IL-6, or IFN-γ. Although TNF has been believed to affect bone primarily by causing osteoclast-driven bone erosion, newer data points to a direct effect of inflammatory mediators on the osteoblast functions as well. Defective bone formation has been reported not only in animal models of IBD (26Dresner-Pollak R. Gelb N. Rachmilewitz D. Karmeli F. Weinreb M. Gastroenterology. 2004; 127: 792-801Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) but also in pediatric Crohn's disease patients (27Hyams J.S. Wyzga N. Kreutzer D.L. Justinich C.J. Gronowicz G.A. J. Pediatr. Gastroenterol. Nutr. 1997; 24: 289-295Crossref PubMed Scopus (124) Google Scholar). Serum from children with Crohn's disease decreases osteoblast function including bone nodule formation in vitro (28Varghese S. Wyzga N. Griffiths A.M. Sylvester F.A. J. Pediatr. Gastroenterol. Nutr. 2002; 35: 641-648Crossref PubMed Scopus (57) Google Scholar).The Phex gene encodes a M13 family of zinc metalloendopeptidase expressed primarily in osteoblasts and odontoblasts. Phenotypically, inborn inactivating mutations in the PHEX gene result in vitamin D resistant, X-linked hypophosphatemic rickets, whereas in vitro, the expression of Phex is a prerequisite for bone matrix deposition (6Kiela P.R. Ghishan F.K. Lab. Invest. 2009; 89: 7-14Crossref PubMed Scopus (51) Google Scholar). We described earlier that chemically induced colitis results in a TNF-mediated decrease in bone Phex expression, and that in vitro exposure of osteoblasts to TNF results in a corresponding decreases of Phex mRNA and protein and a mineralizing defect (19Uno J.K. Kolek O.I. Hines E.R. Xu H. Timmermann B.N. Kiela P.R. Ghishan F.K. Gastroenterology. 2006; 131: 497-509Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). In this report we confirm these observations in more relevant IBD models offered by gnotobiotic IL-10−/− mice and by the naive T-cell transfer, and we identify the molecular mechanism underlying this phenomenon, which likely contributes to dysfunction of osteoblast activity and bone formation in patients with chronic IBD. According to this model, TNF treatment results in the recruitment of the p65/p50 NF-κB complex to two relatively weak cis-elements located at nt −76/−57 and −35/−16 between the Phex transcription start site and a poly(A) element located upstream of the NF-κB sites. Through proteomic and molecular approaches we identified the poly(A)-binding protein as PARP-1, an enzyme participating in TNF-inducible parylation of the p65 (RelA) subunit, likely increasing the affinity of the NF-κB complex to the proximal Phex promoter, resulting in increased retention and inhibited clearance of the RNA polymerase II complex.The obtained results highlight the importance of Phex in osteoblast function during chronic inflammatory conditions, but also the significance of NF-κB activity and the modulating role of PARP-1 in osteoblast function. It also identifies PARP-1 as a potential target in mitigating IBD-associated bone loss. Recent studies using transgenic mice bearing dominant-negative IKK-γ targeted to mature osteoblasts by the bone γ-carboxyglutamate protein-2 (Bglap2) promoter have demonstrated the anti-mineralizing effects of NF-κB (29Chang J. Wang Z. Tang E. Fan Z. McCauley L. Franceschi R. Guan K. Krebsbach P.H. Wang C.Y. Nat. Med. 2009; 15: 682-689Crossref PubMed Scopus (367) Google Scholar). These mice manifested enhanced bone formation with elevated expression of bone matrix genes such as α-1 type 1 collagen, osteocalcin, secreted phosphoprotein-1, and bone sialoprotein. Studies with these transgenic mice also demonstrated that NF-κB is constitutively active, albeit to a lesser extent, under basal conditions (29Chang J. Wang Z. Tang E. Fan Z. McCauley L. Franceschi R. Guan K. Krebsbach P.H. Wang C.Y. Nat. Med. 2009; 15: 682-689Crossref PubMed Scopus (367) Google Scholar). This is consistent with our results that examined mouse promoter activity in UMR-106 cells in the presence of the proteasome inhibitor cLβL. These experiments showed that cLβL alone significantly increases Phex mRNA expression. More importantly, the results from our studies and the IKK dominant-negative transgenic mouse study strongly suggest that targeting NF-κB in the treatment of osteoporosis and inflammatory bone loss will not only result in suppression of bone resorption but also in promotion of bone formation, thus facilitating the rebuilding of bone mass.It is important to note, however, that the role of NF-κB in IBD is very complex and its pleiotropic roles in cellular proliferation, differentiation and survival, inflammation, and carcinogenesis do not make it an easy target for systemic approach (30Karrasch T. Jobin C. Inflamm. Bowel Dis. 2008; 14: 114-124Crossref PubMed Scopus (98) Google Scholar). Identifying PARP-1 as a crucial modulator of NF-κB activity in the osteoblasts opens an alternative possibility of targeting PARP-1. Several lines of evidence suggests that PARP-1 could be a suitable pharmacological target, particularly in IBD. (a) PARP-1 has been shown to participate in triggering the NF-κB pathway, affecting both the classical pathway and the nuclear-to-cytoplasmic DNA damage-induced NF-κB pathway. In the classical pathway, PARP-1 was shown to participate in LPS-induced monocyte chemotactic protein-1 expression (31Oumouna-Benachour K. Hans C.P. Suzuki Y. Naura A. Datta R. Belmadani S. Fallon K. Woods C. Boulares A.H. Circulation. 2007; 115: 2442-2450Crossref PubMed Scopus (85) Google Scholar), whereas in vascular smooth muscle cells PARP-1 was critical for TNF-induced expression of ICAM-1 (but not vascular cell adhesion molecule 1) and shown to physically interact with p65 (RelA) (32Zerfaoui M. Suzuki Y. Naura A.S. Hans C.P. Nichols C. Boulares A.H. Cell. Signal. 2008; 20: 186-194Crossref PubMed Scopus (79) Google Scholar). In the nuclear to cytoplasmic DNA damage-induced NF-κB pathway PARP-1 contributes to the physical assembly of the nuclear signalsome including IKKγ, PIASy (nuclear matrix-associated SUMO E3 ligase), and ATM (protein kinase ataxia telangiectasia mutated) (33Stilmann M. Hinz M. Arslan S.C. Zimmer A. Schreiber V. Scheidereit C. Mol. Cell. 2009; 36: 365-378Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). (b) Modulating PARP-1 expression or enzymatic activity has been shown in numerous studies to ameliorate the symptoms of experimental colitis (34Zingarelli B. Hake P.W. Burroughs T.J. Piraino G. O'Connor M. Denenberg A. Immunology. 2004; 113: 509-517Crossref PubMed Scopus (58) Google Scholar, 35Sánchez-Fidalgo S. Villegas I. Martín A. Sánchez-Hidalgo M. Alarcón de la Lastra C. Eur. J. Pharmacol. 2007; 563: 216-223Crossref PubMed Scopus (40) Google Scholar, 36Di Paola R. Mazzon E. Xu W. Genovese T. Ferraris D. Muià C. Crisafulli C. Zhang J. Cuzzocrea S. Eur. J. Pharmacol. 2005; 527: 163-171Crossref PubMed Scopus (29) Google Scholar, 37Zingarelli B. O'Connor M. Hake P.W. Eur. J. Pharmacol. 2003; 469: 183-194Crossref PubMed Scopus (47) Google Scholar, 38Popoff I. Jijon H. Monia B. Tavernini M. Ma M. McKay R. Madsen K. J. Pharmacol. Exp. Ther. 2002; 303: 1145-1154Crossref PubMed Scopus (40) Google Scholar, 39Jijon H.B. Churchill T. Malfair D. Wessler A. Jewell L.D. Parsons H.G. Madsen K.L. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 279: G641-G651Crossref PubMed Google Scholar).Although PARP-1 is an abundant and ubiquitous nuclear enzyme originally identified as a key factor in the DNA repair pathway, it has now been shown to positively and negatively affect gene transcription and chromatin structure under both basal and signal-activated conditions (40Nguewa P.A. Fuertes M.A. Valladares B. Alonso C. Pérez J.M. Prog. Biophys. Mol. Biol. 2005; 88: 143-172Crossref PubMed Scopus (107) Google Scholar). Studies examining gene expression profiles in PARP-1-deficient embryonic stem cells and liver cells from PARP-1 KO mice showed that 3.5% of the transcriptome were regulated by PARP-1, 70% of which were positively regulated (41Ogino H. Nozaki T. Gunji A. Maeda M. Suzuki H. Ohta T. Murakami Y. Nakagama H. Sugimura T. Masutani M. BMC Genomics. 2007; 8: 41Crossref PubMed Scopus (66) Google Scholar). More notably, PARP-1 has been described as one of the major molecules involved in the propagation of inflammatory stimuli and has been proposed as a target for anti-inflammatory treatment (42Peralta-Leal A. Rodríguez-Vargas J.M. Aguilar-Quesada R. Rodríguez M.I. Linares J.L. de Almodóvar M.R. Oliver F.J. Free Radic. Biol. Med. 2009; 47: 13-26Crossref PubMed Scopus (169) Google Scholar). PARP-1 has been shown to affect gene transcription in several ways: as an enhancer-binding factor similar to classical sequence-specific DNA-binding activators or repressors, as a transcriptional co-regulator, or as a modifying enzyme that catalyzes the NAD+-dependent addition of ADP(ribose) polymers (PARylation) to several nuclear proteins. We demonstrate here that in TNF-treated osteoblasts, RelA is translocated to the nucleus, where it is PARylated by PARP-1. This chemical modification is critical for TNF-induced inhibition of Phex expression because this response does not occur in PARP-1-deficient mice and is reversed by the PARP-1 inhibitor 3-AB or by an overexpression of PARG. Although it is technically challenging to determine whether PARP-1 and RelA physically interact with each other in the context of the Phex gene promoter, the proximity of their binding sites and inducible recruitment of RelA suggest such a possibility.Interestingly, we initially described the Phex poly(A) promoter region as a positive cis-element whose affinity for a 110 kDa, then unidentified binding protein was decreased in response to dihydroxy-vitamin D treatment (29Chang J. Wang Z. Tang E. Fan Z. McCauley L. Franceschi R. Guan K. Krebsbach P.H. Wang C.Y. Nat. Med. 2009; 15: 682-689Crossref PubMed Scopus (367) Google Scholar). Although the exact mechanism of the effects of vitamin D on PARP-1 in osteoblasts requires further work, our findings suggest that PARP-1 may play a pleiotropic role in the regulation of Phex gene transcription, depending on the physiological or pathophysiological context.In conclusion, our results describe a new mechanism of TNF-mediated gene regulation in osteoblasts involving NF-κB and PARP-1. Cooperatively, NF-κB signaling and PARP-1 enzymatic activity constitutively and inducibly suppress Phex gene expression. IntroductionBones have several physiological functions including maintaining organism structure, serving as a hematopoietic niche, calcium and inorganic phosphate reservoir, and regulating and feeding back to other organs via hormone release. To balance both normal serum mineral concentrations and bone mineral density, bones have a dynamic homeostasis that involve bone-forming osteoblasts and bone-resorbing osteoclasts. This balance is influenced by hormones, neurotransmitters, and cytokines that act directly on osteoblasts and osteoclasts to affect mineral deposition and release (1Caetano-Lopes J. Canhão H. Fonseca J.E. Autoimmun. Rev. 2009; 8: 250-255Crossref PubMed Scopus (113) Google Scholar).Although normal bone structure is the result of the balance of these two opposite processes, certain genetic disorders can skew this balance leading to low bone mineralization. In vitamin D-resistant, X-linked hypophosphatemic rickets, an inactivating mutation of PHEX 3The abbreviations used are: PHEXphosphate-regulating gene with homologies to endopeptidases on the X chromosomeIBDinflammatory bowel diseasePARP-1poly(ADP-ribose) polymerase 1PARGpoly(ADP-ribose) glycohydrolaseDAPADNA affinity precipitation assayRNAP IIRNA polymerase IITSStranscriptional start site3-AB3-aminobenzamidecLβLclasto-lactacystin-β-lactonentnucleotide(s)SPFspecific pathogen freeNPnuclear proteinCHXcycloheximideICAM-1intercellular adhesion molecule 1PMPparamagnetic particlesKOknock-out. (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) leads to hypophosphatemia, aberrant vitamin D levels, high serum alkaline phosphatase, and osteomalacia (2Francis F. Hennig S. Korn B. Reinhardt R. de Jong P. Poustka A. Lehrach H. Rowe P.S. Goulding J.N. Summerfield T. Mountford R. Read A.P. Popowska E. Pronicka E. Davies K.E. O'Riordan J.L. Econs M.J. Nesbitt T. Drezner M.K. Oudet C. Pannetier S. Hanauer A. Strom T.M. Meindl A. Lorenz B. Cagnoli B. Mohnike K.L. Murken J. Meitinger T. Nat. Genet. 1995; 11: 130-136Crossref PubMed Scopus (957) Google Scholar, 3Strom T.M. Francis F. Lorenz B. Böddrich A. Econs M.J. Lehrach H. Meitinger T. Hum. Mol. Genet. 1997; 6: 165-171Crossref PubMed Scopus (174) Google Scholar). Although the Phex gene encodes a membrane-bound, zinc metallopeptidase expressed only in osteoblasts and odontoblasts, the effects of its mutation lead to phosphate wasting in the kidney by decreasing the expression and activity of the Na+/Pi cotransporter, NaPi-IIa (NPT2; SLC24A1) in proximal convoluted tubules (4Collins J.F. Scheving L.A. Ghishan F.K. Am. J. Physiol. Renal Physiol. 1995; 269: F439-F448Crossref PubMed Google Scholar, 5Tenenhouse H.S. Annu. Rev. Nutr. 2005; 25: 197-214Crossref PubMed Scopus (146) Google Scholar). Phex inactivation was postulated to indirectly affect the kidney through bone-released, phosphaturic factors known as phosphatonins. Fibroblast growth factor 23 (FGF23) was one of the leading phosphatonin candidates due to its potent negative effects on renal phosphate reabsorption and its highly elevated expression in X-linked hypophosphatemic ricket patients (6Kiela P.R. Ghishan F.K. Lab. Invest. 2009; 89: 7-14Crossref PubMed Scopus (51) Google Scholar). Although initial studies seemed to confirm this mechanism (7Bowe A.E. Finnegan R. Jan de Beur S.M. Cho J. Levine M.A. Kumar R. Schiavi S.C. Biochem. Biophys. Res. Commun. 2001; 284: 977-981Crossref PubMed Scopus (294) Google Scholar), it was later shown that Phex mutations lead to increased FGF23 expression rather than processing (8Liu S. Guo R. Simpson L.G. Xiao Z.S. Burnham C.E. Quarles L.D. J. Biol. Chem. 2003; 278: 37419-37426Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar), and that FGF23 is cleaved by subtilisin-like proprotein convertases and not PHEX (9Benet-Pagès A. Lorenz-Depiereux B. Zischka H. White K.E. Econs M.J. Strom T.M. Bone. 2004; 35: 455-462Crossref PubMed Scopus (208) Google Scholar).In addition to the renal abnormalities in X-linked hypophosphatemic rickets, PHEX inactivation also leads to osteoblast mineralization deficits. This is exemplified by the inability of immortalized osteoblasts from Phex-deficient Hyp mice to mineralize in vitro (10Xiao Z.S. Crenshaw M. Guo R. Nesbitt T. Drezner M.K. Quarles L.D. Am. J. Physiol. Endocrinol. Metab. 1998; 275: E700-E708Crossref PubMed Google Scholar). Although the target(s) of PHEX proteolytic activity remains uncertain, PHEX protein may influence bone metabolism by binding and stabilizing matrix extracellular phosphoglycoprotein, dentine matrix protein 1 (DMP1) (11Martin A. David V. Laurence J.S. Schwarz P.M. Lafer E.M. Hedge A.M. Rowe P.S. Endocrinology. 2008; 149: 1757-1772Crossref PubMed Scopus (138) Google Scholar), and osteopontin (12Addison W. Masica D. Gray J. McKee M.D. J. Bone Miner. Res. 2010; 25: 695-705Crossref PubMed Scopus (15) Google Scholar). Specifically, when PHEX binds to these substrates, it prevents their cleavage and release of a small, acidic protease-resistant ASARM peptide (acidic serine-aspartate-rich matrix extracellular phosphoglycoprotein-associated motif). These ASARM peptides have been shown to inhibit mineralization in vivo and in vitro, and most likely function by directly binding to hydroxyapatite crystals and by decreasing the expression of Phex (13Addison W.N. Nakano Y. Loisel T. Crine P. McKee M.D. J. Bone Miner Res. 2008; 23: 1638-1649Crossref PubMed Scopus (158) Google Scholar).PHEX itself is regulated by several hormones and cytokines important for skeletal homeostasis. Phex is up-regulated after treatment with insulin-like growth factor 1, growth hormone (14Zoidis E. Gosteli-Peter M. Ghirlanda-Keller C. Meinel L. Zapf J. Schmid C. Eur. J. Endocrinol. 2002; 146: 97-105Crossref PubMed Scopus (43) Google Scholar), and glucocorti" @default.
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