BoneKEy-Osteovision | Not To Be Missed

Clinical and basic research papers – November 2005 selections

DOI:10.1138/20050186

Bone modeling and remodeling

◆ Clark WD, Smith EL, Linn KA, Paul-Murphy JR, Muir P, Cook ME. Osteocyte apoptosis and osteoclast presence in chicken radii 0-4 days following osteotomy. Calcif Tissue Int. 2005 Nov;77(5):327–36.

Osteocytes may be the leaders of the orchestra of local remodeling. The reason remodeling occurs at a given focal point on a bone surface is not known, but remodeling is thought to be induced by local damage, which in turn produces osteocyte apoptosis. The extent and anatomy of apoptosis may provide the road map needed to localize damage and then signal osteoclastogenesis and osteoblastogenesis for the removal of damaged bone and restoration with new bone. In this study, the incidence of osteocyte apoptosis and the presence of osteoclasts during the first 96 hours following osteotomy were assessed. Osteocyte apoptosis precedes an increase in osteoclast presence. —ES

◆ Hilton MJ, Tu X, Cook J, Hu H, Long F. Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Development 2005 Oct 1;132(19):4339–51.

◆ Koziel L, Wuelling M, Schneider S, Vortkamp A. Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation. Development. 2005 Dec;132 (23):5249–60.

Indian hedgehog (Ihh) is a regulator of cartilage maturation and endochondral ossification. In general, hedgehogs act on Gli family transcription factors, either by counteracting their repression of gene expression or by inducing their transcriptional activity. These two papers examine the results of removing the Gli3 gene from Ihh(-/-) embryos. Most of the cartilage phenotype of Ihh deficiency is restored by removing Gli3: chondrocytes proliferate relatively normally and no longer undergo premature hypertrophy. This indicates that Ihh acts in cartilage mainly by blocking repression of gene expression by Gli3. Koziel et al. report that restoration of normal chondrocyte hypertrophy is PTHrP dependent, but the switch from distal into columnar proliferating chondrocytes is PTHrP-independent. Hilton et al. concentrate on the persistent failure of bone collar formation in double knockouts and conclude that an activator activity of Gli3 and a vasculature-derived signal are required for osteoblast development. —GJS

◆ Kieslinger M, Folberth S, Dobreva G, Dorn T, Croci L, Erben R, Consalez GG, Grosschedl R. EBF2 Regulates Osteoblast-Dependent Differentiation of Osteoclasts. Dev Cell. 2005 Dec;9(6):757–67.

This paper implicates the transcription factor EBF2 in the regulation of osteoprotegerin expression by osteoblasts. Contrary to cbfa1/Runx2 and Osterix KO mice, EBF2 KO mice have a normal skeletal morphology at birth, but develop dwarfism and a dramatic reduction of cortical thickness and trabecular volume by 3 weeks of age. Bone formation and osteoblast numbers are normal in these mice, and there is no evidence for an osteoblast-autonomous defect in vitro. In contrast, osteoclast numbers are increased, as well as biochemical indices of bone resorption. OPG mRNA expression is decreased and RANKL mRNA is more modestly increased in EBF2-deficient osteoblasts. Subsequently, EBF binding sites in the OPG promoter region were identified and, most interestingly, EBF2 was shown to synergize with beta-catenin, the mediator of the canonical Wnt signaling pathway, for the transcriptional control of OPG. —SF

◆ van der Eerden BC, Hoenderop JG, de Vries TJ, Schoenmaker T, Buurman CJ, Uitterlinden AG, Pols HA, Bindels RJ, van Leeuwen JP. The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption. Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17507–12.

The epithelial calcium channel transient receptor potential-5 (TRPV5) is the PTH- and vitamin D-responsive channel through which calcium is reabsorbed in the distal nephron. This paper reports that osteoclasts display TRPV5 in the ruffled border, and that osteoclasts from which the TRPV5 gene was removed are deficient in bone resorption. Impaired bone resorption in TRPV5(-/-) mice is not associated with full-blown osteopetrosis, however, perhaps because of markedly increased 1,25(OH)2D levels in TRPV5(-/-) mice, or because osteoclasts also express the vitamin D-sensitive intestinal brush border calcium channel TRPV6. Calcium transport through TRPV channels is physiologically significant in kidney, intestine and bone. —GJS

Diagnosis

◆ Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005 Dec;90(12):6508–15.

The use of high-resolution micro-computed tomography (HRmCT) to analyze tri-dimensional trabecular and cortical bone architecture in vivo is moving from rodents to humans. This seminal paper describes the excellent reproducibility of this technology in adults. Consistent with previous bone histomorphometrical analyses performed on iliac crest biopsies, HRmCT shows a rather large decrease in trabecular and cortical bone parameters at distal radius and tibia in osteopenic and osteoporotic women, as compared to premenopausal women. Most interestingly, trabecular architecture at the distal radius, but not tibia, was significantly decreased in a subgroup of osteopenic postmenopausal women with a history of non-vertebral fractures, compared to those without such history. It now remains to be seen whether non-invasive peripheral measurements of bone micro-architecture will be able to discriminate osteopenic women with or without vertebral fractures as well. —SF

Pathophysiology

◆ Sun L, Blair HC, Peng Y, Zaidi N, Adebanjo OA, Wu XB, Wu XY, Iqbal J, Epstein S, Abe E, Moonga BS, Zaidi M. Calcineurin regulates bone formation by the osteoblast. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17130–35.

Calcium signals transmitted by the calcium-sensitive protein phosphatase calcineurin are essential for T-lymphocyte and osteoclast function. Immunosuppression with calcineurin inhibitors, such as cyclosporin A and tacrolimus (FK506), is associated with severe osteoporosis. Mice lacking the gene for the subunit calcineurin Aα have severe osteoporosis, with markedly reduced bone formation. Runx2, osteocalcin and bone sialoprotein expression are reduced in calcineurin Aα (-/-) osteoblasts; transduction of calcineurin Aα into osteoblasts enhances their expression. Similar findings were reported in mice deficient in NFAT, a transcription factor that is downstream of calcineurin (Koga T. et al., Nat Med. 2005 Aug;11(8):880–5). —GJS

Physiology and metabolism

◆ Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology. 2005 Dec;146(12):5358–64.

FGF-23 is one of the “phosphatonins” that promotes tubular excretion of phosphate and inhibits synthesis of calcitriol. Some human studies have shown that circulating FGF-23 increases upon introduction of a phosphate-rich diet, and conversely decreases upon phosphate deprivation, thereby demonstrating phosphate homeostasis regulation independent of PTH. This study now provides further evidence that dietary phosphate regulates circulating FGF-23 levels and that FGF-23 is directly correlated to serum phosphate levels in mice. Furthermore, FGF-23 mRNA abundance, in calvarial bone, followed the pattern of circulating FGF-23 in response to diet, indicating that bone may be an important source of FGF-23 in response to phosphate changes. —SF

◆ Ryan MR, Shepherd R, Leavey JK, Gao Y, Grassi F, Schnell FJ, Qian WP, Kersh GJ, Weitzmann MN, Pacifici R. An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency. Proc Natl Acad Sci U S A. 2005 Nov 15;102 (46):16735–40.

Estrogen deficiency causes rapid bone loss; however, the role of local and systemic cytokines in this phenomenon is uncertain. Here, it is reported that ovariectomy (OVX) leads to dysregulation of T-cell development, stimulating more thymic maturation of bone marrow-derived T-cell progenitors. The key signal to induce thymic T-cell maturation is interleukin-7 (IL-7). Thymectomy reduces post-OVX bone loss by about half, but blocking IL-7 completely prevents it, suggesting that IL-7 has both thymic and extrathymic actions to induce immune functions related to estrogen-responsive bone loss. —GJS

Treatment and drug effects

◆ Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA. Nov 2005;294(18):2336–41.

That vitamin D insufficiency causes secondary hyperparathyroidism is now well-established. This large cross-sectional study in Iceland shows the expected inverse relationship of 25-hydroxyvitamin D [25(OH)D] and PTH, but also shows that at 25(OH)D levels <10 ng/ml, subjects with estimated calcium intakes <800 mg/day had secondary hyperparathyroidism, but those with intakes >1200 mg/day did not. In subjects with 25(OH)D levels >18 ng/ml, there was no relationship between calcium intake and PTH, suggesting that when vitamin D intake is adequate, calcium intake levels of more than 800 mg/day may be unnecessary to maintain calcium homeostasis. Vitamin D supplementation is required to maintain these levels, however, in this northern climate. —GJS

Reviews, perspectives and editorials

◆ Balemans W, Van Wesenbeeck L, Van Hul W. A clinical and molecular overview of the human osteopetroses. Calcif Tissue Int. 2005 Nov;77(5):263–74.

◆ Blake GM, Fogelman I. Long-term effect of strontium ranelate treatment on BMD. J Bone Miner Res. 2005 Nov;20(11):1901–4.

◆ Conroy S, O'Malley B. Hypercalcaemia in cancer. BMJ. 2005 Oct 22;331(7522):954.

◆ Fleurence RL, Iglesias CP, Torgerson DJ. Economic evaluations of interventions for the prevention and treatment of osteoporosis: a structured review of the literature. Osteoporos Int. 2006 Jan;17(1):29–40.

◆ Franchimont N, Wertz S, Malaise M. Interleukin-6: an osteotropic factor influencing bone formation. Bone. 2005 Nov;37(5):601–6.

◆ Jacobs TP, Bilezikian JP. Rare causes of hypercalcemia. J Clin Endocrinol Metab. 2005 Nov 1;90(11):6316–22.

◆ Levin A, Li YC. Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease. Kidney Int. Nov 2005;68(5):1973–81.

◆ Loberg RD, Logothetis CJ, Keller ET, Pienta KJ. Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype. J Clin Oncol. 2005 Nov 10;23(32):8232–41.

◆ Michaelson MD, Smith MR. Bisphosphonates for treatment and prevention of bone metastases. J Clin Oncol. 2005 Nov 10;23(32):8219–24.

◆ Morris HA. Vitamin D: A hormone for all seasons - how much is enough? Understanding the new pressures. Clin Biochem Rev. Feb 2005;26(1):21–32.

◆ Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC. Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know. Endocr Rev. 2005 Dec;26(7):898–915.

◆ Rogers A, Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab. 2005 Nov 1;90(11):6323–31.

◆ Rosen CJ, Brown SA. A rational approach to evidence gaps in the management of osteoporosis. Am J Med. 2005 Nov;118(11):1183–9.

◆ Speroff L. Alternative therapies for postmenopausal women. Int J Fertil Womens Med. May 2005;50(3):101–14.

◆ Takayanagi H, Sato K, Takaoka A, Taniguchi T. Interplay between interferon and other cytokine systems in bone metabolism. Immunol Rev. 2005 Dec;208:181–93.

◆ Townsend K, Evans KN, Campbell MJ, Colston KW, Adams JS, Hewison M. Biological actions of extra-renal 25-hydroxyvitamin D-1alpha-hydroxylase and implications for chemoprevention and treatment. J Steroid Biochem Mol Biol. Oct 2005;97(1-2):103–9.

◆ Wilkins CH, Birge SJ. Prevention of osteoporotic fractures in the elderly. Am J Med. 2005 Nov;118(11):1190–5.

Other studies of potential interest

◆ Ai M, Heeger S, Bartels CF, Schelling DK; Osteoporosis-Pseudoglioma Collaborative Group. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet. 2005 Nov;77(5):741–53.

◆ Almeida M, Han L, Bellido T, Manolagas SC, Kousteni S. Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/Akt. J Biol Chem. 2005 Dec 16;280(50):41342–51.

◆ Castro M, Nikolaev VO, Palm D, Lohse MJ, Vilardaga JP. Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16084–9.

◆ Clément-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssière B, Belleville C, Estrera K, Warman ML, Baron R, Rawadi G. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17406–11.

◆ Conway JG, McDonald B, Parham J, Keith B, Rusnak DW, Shaw E, Jansen M, Lin P, Payne A, Crosby RM, Johnson JH, Frick L, Lin MH, Depee S, Tadepalli S, Votta B, James I, Fuller K, Chambers TJ, Kull FC, Chamberlain SD, Hutchins JT. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078–83.

◆ de Souza RL, Pitsillides AA, Lanyon LE, Skerry TM, Chenu C. Sympathetic nervous system does not mediate the load-induced cortical new bone formation. J Bone Miner Res. 2005 Dec;20(12):2159–68.

◆ Henriksen K, Gram J, Hoegh-Andersen P, Jemtland R, Ueland T, Dziegiel MH, Schaller S, Bollerslev J, Karsdal MA. Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo. Am J Pathol. 2005 Nov;167(5):1341–8.

◆ Ijiri K, Zerbini LF, Peng H, Correa RG, Lu B, Walsh N, Zhao Y, Taniguchi N, Huang XL, Otu H, Wang H, Wang JF, Komiya S, Ducy P, Rahman MU, Flavell RA, Gravallese EM, Oettgen P, Libermann TA, Goldring MB. A novel role for GADD45beta as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. J Biol Chem. 2005 Nov 18;280(46):38544–55.

◆ Kim K, Kim JH, Lee J, Jin HM, Lee SH, Fisher DE, Kook H, Kim KK, Choi Y, Kim N. Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activation-induced cytokine-mediated osteoclastogenesis. J Biol Chem. 2005 Oct 21;280(42):35209–16.

◆ Kitaura H, Zhou P, Kim HJ, Novack DV, Ross FP, Teitelbaum SL. M-CSF mediates TNF-induced inflammatory osteolysis. J Clin Invest. 2005 Dec;115(12):3418–27.

◆ Kugimiya F, Kawaguchi H, Kamekura S, Chikuda H, Ohba S, Yano F, Ogata N, Katagiri T, Harada Y, Azuma Y, Nakamura K, Chung UI. Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation. J Biol Chem. 2005 Oct 21;280(42):35704–12.

◆ Miyauchi Y, Michigami T, Sakaguchi N, Sekimoto T, Yoneda Y, Pike JW, Yamagata M, Ozono K. Importin 4 is responsible for ligand-independent nuclear translocation of vitamin D receptor. J Biol Chem. 2005 Dec 9;280(49):40901–8.

◆ Pi M, Faber P, Ekema G, Jackson PD, Ting A, Wang N, Fontilla-Poole M, Mays RW, Brunden KR, Harrington JJ, Quarles LD. Identification of a novel extracellular cation-sensing G-protein-coupled receptor. J Biol Chem. 2005 Dec 2;280(48):40201–9.

◆ Rios H, Koushik SV, Wang H, Wang J, Zhou HM, Lindsley A, Rogers R, Chen Z, Maeda M, Kruzynska-Frejtag A, Feng JQ, Conway SJ. Periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype. Mol Cell Biol. 2005 Dec;25(24):11131–44.

◆ Ross CM. Dairy, vitamin D, and type 2 diabetes mellitus. Arch Intern Med. 2005 Nov 14;165(20):2434.

◆ Schneeweis LA, Willard D, Milla ME. Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-kappaB ligand. J Biol Chem. 2005 Dec 16;280(50):41155–64.

◆ Shin CS, Her SJ, Kim JA, Kim do H, Kim SW, Kim SY, Kim HS, Park KH, Kim JG, Kitazawa R, Cheng SL, Civitelli R. Dominant negative N-cadherin inhibits osteoclast differentiation by interfering with beta-catenin regulation of RANKL, independent of cell-cell adhesion. J Bone Miner Res. Dec 2005;20(12):2200–12.

◆ Shinohara ML, Jansson M, Hwang ES, Werneck MB, Glimcher LH, Cantor H. T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17101–6.

◆ Silve C, Petrel C, Leroy C, Bruel H, Mallet E, Rognan D, Ruat M. Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor. J Biol Chem. 2005 Nov 11;280(45):37917–23.

◆ Stickens D, Zak BM, Rougier N, Esko JD, Werb Z. Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development. 2005 Nov 15;132(22):5055–68.

◆ Verlinden L, Eelen G, Beullens I, Van Camp M, Van Hummelen P, Engelen K, Van Hellemont R, Marchal K, De Moor B, Foijer F, Te Riele H, Beullens M, Bollen M, Mathieu C, Bouillon R, Verstuyf A. Characterization of the condensin component Cnap1 and protein kinase Melk as novel E2F target genes down-regulated by 1,25-dihydroxyvitamin D3. J Biol Chem. 2005 Nov 11;280(45):37319–30.

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