Hypoxia-inducible factor-1α restricts the anabolic actions of parathyroid hormone

Abstract

The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1α in osteoanabolic signaling, we assessed the effect of Hif-1α loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1α in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1α protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1α-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1α functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1α function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.

Osteoporosis: Novel target could improve treatment

US researchers have identified a novel target that could enhance the effects of parathyroid hormone (PTH) in the treatment of osteoporosis. A group led by Ryan Riddle at the Johns Hopkins University looked at factors that influence bone turnover at the cellular level in response to PTH. They found a rapid accumulation of bone occurred when they gave PTH to mutant mice lacking the regulatory protein hypoxia-inducible factor 1-alpha (Hif-1α). As bone matures, Hif-α interferes with cellular pathways which increase bone formation through its interaction with the protein β-catenin. The authors conclude that drugs that inhibit Hif-1α or impair the interaction of Hif-1α with β-catenin could be used to lower the therapeutic dose of PTH. This would increase bone accumulation and reduce the risk of fracture in patients with osteoporosis.

References

[1] Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev, 1993, 14: 690-709

[2] Finkelstein JS, Klibanski A, Schaefer EH, Hornstein MD, Schiff I, Neer RM. Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. N Engl J Med, 1994, 331: 1618-1623

[3] Hansen S, Hauge EM, Beck Jensen JE, Brixen K. Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: an 18-month open-labeled observational study using HR-pQCT. J Bone Miner Res, 2013, 28: 736-745

[4] Kurland ES, Cosman F, McMahon DJ, Rosen CJ, Lindsay R, Bilezikian JP. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab, 2000, 85: 3069-3076

[5] Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone, 2007, 40: 1434-1446

[6] Abou-Samra AB, Juppner H, Force T et al Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci USA, 1992, 89: 2732-2736

[7] Iida-Klein A, Zhou H, Lu SS et al Anabolic action of parathyroid hormone is skeletal site specific at the tissue and cellular levels in mice. J Bone Miner Res, 2002, 17: 808-816

[8] Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology, 1997, 138: 4607-4612

[9] Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest, 1999, 104: 439-446

[10] Wu X, Pang L, Lei W et al Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling. Cell Stem Cell, 2010, 7: 571-580

[11] Dobnig H, Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology, 1995, 136: 3632-3638

[12] Rodan SB, Rodan GA. The effect of parathyroid hormone and thyrocalcitonin on the accumulation of cyclic adenosine 3′:5′-monophosphate in freshly isolated bone cells. J Biol Chem, 1974, 249: 3068-3074

[13] Wang Y, Nishida S, Boudignon BM et al IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone. J Bone Miner Res, 2007, 22: 1329-1337

[14] Yakar S, Bouxsein ML, Canalis E et al The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone. J Endocrinol, 2006, 189: 289-299

[15] Yamaguchi M, Ogata N, Shinoda Y et al Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice. Endocrinology, 2005, 146: 2620-2628

[16] Qiu T, Wu X, Zhang F, Clemens TL, Wan M, Cao X. TGF-beta type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat Cell Biol, 2010, 12: 224-234

[17] Li C, Xing Q, Yu B et al Disruption of LRP6 in osteoblasts blunts the bone anabolic activity of PTH. J Bone Miner Res, 2013, 28: 2094-2108

[18] Robling AG, Kedlaya R, Ellis SN et al Anabolic and catabolic regimens of human parathyroid hormone 1–34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology, 2011, 152: 2963-2975

[19] Robling AG, Childress P, Yu J et al Nmp4/CIZ suppresses parathyroid hormone-induced increases in trabecular bone. J Cell Physiol, 2009, 219: 734-743

[20] Childress P, Philip BK, Robling AG et al Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts. Calcif Tissue Int, 2011, 89: 74-89

[21] Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell, 2012, 148: 399-408

[22] Semenza GL. HIF-1, O₂, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell, 2001, 107: 1-3

[23] Mole DR, Blancher C, Copley RR et al Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem, 2009, 284: 16767-16775

[24] Kulshreshtha R, Ferracin M, Wojcik SE et al A microRNA signature of hypoxia. Mol Cell Biol, 2007, 27: 1859-1867

[25] Shomento SH, Wan C, Cao X et al Hypoxia-inducible factors 1α and 2α exert both distinct and overlapping functions in long bone development. J Cell Biochem, 2010, 109: 196-204

[26] Wang Y, Wan C, Deng L et al The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest, 2007, 117: 1616-1626

[27] Riddle RC, Leslie JM, Gross TS, Clemens TL. Hypoxia-inducible factor-1α protein negatively regulates load-induced bone formation. J Biol Chem, 2011, 286: 44449-44456

[28] Akeno N, Robins J, Zhang M, Czyzyk-Krzeska MF, Clemens TL. Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2α. Endocrinology, 2002, 143: 420-425

[29] Niziolek PJ, Murthy S, Ellis SN et al Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatment. J Cell Physiol, 2009, 221: 579-585

[30] Prisby R, Guignandon A, Vanden-Bossche A et al Intermittent PTH(1–84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites. J Bone Miner Res, 2011, 26: 2583-2596

[31] Zhang M, Xuan S, Bouxsein ML et al Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem, 2002, 277: 44005-44012

[32] Ryan HE, Lo J, Johnson RS. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J, 1998, 17: 3005-3015

[33] Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. Acute postnatal ablation of Hif-2α results in anemia. Proc Natl Acad Sci USA, 2007, 104: 2301-2306

[34] Haase VH, Glickman JN, Socolovsky M, Jaenisch R. Vascular tumors in livers with targeted inactivation of the von Hippel–Lindau tumor suppressor. Proc Natl Acad Sci USA, 2001, 98: 1583-1588

[35] Lang CH, Frost RA, Bronson SK, Lynch CJ, Vary TC. Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine. Am J Physiol Endocrinol Metab, 2010, 298: E1283-E1294

[36] Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res, 2010, 25: 1468-1486

[37] Dempster DW, Compston JE, Drezner MK et al Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res, 2013, 28: 2-17

[38] Parfitt AM, Drezner MK, Glorieux FH et al Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res, 1987, 2: 595-610

[39] Land SC, Tee AR. Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem, 2007, 282: 20534-20543

[40] Hudson CC, Liu M, Chiang GG et al Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol, 2002, 22: 7004-7014

[41] Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F. Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol, 2002, 22: 1172-1183

[42] Milkiewicz M, Doyle JL, Fudalewski T, Ispanovic E, Aghasi M, Haas TL. HIF-1α and HIF-2α play a central role in stretch-induced but not shear-stress-induced angiogenesis in rat skeletal muscle. J Physiol, 2007, 583: 753-766

[43] Liu XH, Kirschenbaum A, Lu M et al Prostaglandin E2 induces hypoxia-inducible factor-1α stabilization and nuclear localization in a human prostate cancer cell line. J Biol Chem, 2002, 277: 50081-50086

[44] Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol, 2002, 64: 993-998

[45] Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev, 2000, 14: 1983-1991

[46] Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res, 1999, 59: 3915-3918

[47] Yamashita R, Suzuki Y, Takeuchi N et al Comprehensive detection of human terminal oligo-pyrimidine (TOP) genes and analysis of their characteristics. Nucleic Acids Res, 2008, 36: 3707-3715

[48] Blancquaert S, Wang L, Paternot S et al cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4. Mol Endocrinol, 2010, 24: 1453-1468

[49] Alam H, Maizels ET, Park Y et al Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation. J Biol Chem, 2004, 279: 19431-19440

[50] Brugarolas J, Lei K, Hurley RL et al Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev, 2004, 18: 2893-2904

[51] Simon MC. Mitochondrial reactive oxygen species are required for hypoxic HIF α stabilization. Adv Exp Med Biol, 2006, 588: 165-170

[52] Brunelle JK, Bell EL, Quesada NM et al Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab, 2005, 1: 409-414

[53] Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab, 2006, 3: 177-185

[54] Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab, 2006, 3: 187-197

[55] Wong CC, Zhang H, Gilkes DM et al Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J Mol Med (Berl), 2012, 90: 803-815

[56] Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci USA, 2009, 106: 17910-17915

[57] Zhang H, Qian DZ, Tan YS et al Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc Natl Acad Sci USA, 2008, 105: 19579-19586

[58] Girotra M, Rubin MR, Bilezikian JP. The use of parathyroid hormone in the treatment of osteoporosis. Rev Endocr Metab Disord, 2006, 7: 113-121

[59] Rubin MR, Bilezikian JP. The anabolic effects of parathyroid hormone therapy. Clin Geriatr Med, 2003, 19: 415-432