BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers – December 2006 selections
DOI:10.1138/20060243
Bone modeling and remodeling◆ Gao Y, Grassi F, Ryan MR, Terauchi M, Page K, Yang X, Weitzmann MN, Pacifici R. IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest. 2007 Jan;117(1):122–32.
The role of interferon-γ on bone resorption is complex and somewhat controversial. Numerous experiments in mice and humans indicate that on one side IFN-γ promotes osteoclastogenesis, on the other that IFN-γ inhibits RANKL effects on osteoclast formation. Through a series of elegant experiments in vitro and in vivo, the authors demonstrate here that IFN-γ may exert dual (both positive and negative) effects on bone resorption via direct inhibition of osteoclastogenesis, and indirect stimulation of osteoclastogenesis through T cell activation. Yet, IFN-γ receptor KO mice were only partially resistant against bone loss induced by ovariectomy or LPS, suggesting that IFN-γ acts as a modulator, rather than as a key factor, for bone resorption. —SF
◆ Haycraft CJ, Zhang Q, Song B, Jackson WS, Detloff PJ, Serra R, Yoder BK. Intraflagellar transport is essential for endochondral bone formation. Development. 2007 Jan;134(2):307–16.
The finding that cilia are important to bone remodeling has caused a considerable flurry (see BoneKEy-Osteovision. 2006 December;3(12):7-10). Haycroft et al. used a conditional allele of the polaris gene product to disrupt cilia within the developing limb. Deletion of cilia from ectoderm had no overt effect, but removal of cilia from the mesenchyme caused aberrant sonic hedgehog and Indian hedgehog signaling, with digit patterning and limb outgrowth abnormalities, respectively. Moreover, elements of the perichondrium differentiate abnormally into chondrocyte-like cells. Cilia are important in limb patterning and endochondral bone formation. —GJS
◆ Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P. Non-enzymatic glycations of bone collagen modify osteoclastic activity and differentiation. J Biol Chem. 2006 Dec 1; [Epub ahead of print]
It is interesting when the result is diametrically opposite to that hypothesized. Advanced glycation end products (AGEs) appear to inhibit bone resorption. Mature osteoclasts seeded on slices containing an AGE result in a reduction in resorbed area, and decreased release of type I collagen fragments. —ES
Genetics◆ Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, Leikin S, Makareeva E, Kuznetsova N, Uveges TE, Ashok A, Flor AW, Mulvihill JJ, Wilson PL, Sundaram UT, Lee B, Marini JC. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med. 2006 Dec 28;355(26):2757–64.
Three children with lethal or severe osteogenesis imperfecta but no primary collagen mutations were shown to have mutations in the gene for cartilage-associated protein (CRTAP), part of the prolyl 3-hydroxylase complex. All had deficient 3-hydroxylation of Pro986 and excessive posttranslational modification of collagen, consistent with delayed folding of the collagen gene. A similar syndrome results from deletion of the mouse gene for CRTAP (see Morello et al. Cell. 2006 Oct;127(2):291-304). Though the obvious conclusion would be that 3-hydroxylation is essential for normal collagen folding, in a recent Commentary (see BoneKEy-Osteovision. 2006 November;3(11):10-13), Stephen Krane discusses the pathogenesis of osteogenesis imperfecta in these syndromes and suggests that deficient 3-hydroxylation of Pro986 may not be the whole story. —GJS
Pathophysiology◆ Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, Gu K, Shah V, Pei L, Zarbo RJ, McCauley L, Shi S, Chen S, Wang CY. NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med. 2007 Jan;13(1):62–9.
Metastatic MDA-MB-231 breast cancer cells express NF-κB, and inhibiting the NF-κB pathway by expression of a super-repressor (MDA/I cells) or with IKK2 inhibitors prevents osteolytic bone metastasis. A principal target gene of the NF-κB pathway in MDA cells is GM-CSF; restoration of GM-CSF expression in MDA/I cells restores their ability to metastasize to bone. It is GM-CSF produced by MDA cells that is responsible for osteoclastogenesis in vitro; knockdown of GM-CSF reduces osteolytic bone metastasis, and also inhibits osteolysis by MDA cells injected directly into bone. Importantly, 75% of bone metastatic human breast cancers display nuclear localization of NF-κB and express GM-CSF. Though there are many candidate mediators of tumor osteolysis, the GM-CSF story told here is remarkably complete. —GJS
◆ Sornay-Rendu E, Boutroy S, Munoz F, Delmas PD. Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased bone mineral density measured by DXA. The OFELY study. J Bone Miner Res. 2006 Dec 20; [Epub ahead of print]
These authors previously reported in a smaller sample of postmenopausal women that volumetric bone density and trabecular structure at the distal radius, as evaluated by high-resolution computed tomography, was decreased in women with fractures compared to women without fractures, despite similar levels of BMD. In this study, they compared a larger sample of women with and without fractures prospectively assessed for up to 13 years, confirming their previous data and further indicating that some parameters of bone microarchitecture, such as trabecular density at the distal radius and cortical thickness at the distal tibia, remain lower among fractured women after adjusting for BMD values at ultradistal radius and total hip, respectively. —SF
Treatment and drug effects◆ Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927–38.
◆ Colon-Emeric CS. Ten vs five years of bisphosphonate treatment for postmenopausal osteoporosis: enough of a good thing. JAMA. 2006 Dec 27;296(24):2968–9.
1099 postmenopausal women were randomized to alendronate or placebo for 5 years after 5 years of alendronate. Despite declines in BMD and increases in markers of turnover, non-vertebral and morphometric vertebral fractures were no greater in the placebo group. There was a lower risk of clinical vertebral fractures with continued alendronate. The null observation is interpreted as being consistent with a sustained protective effect after discontinuation of alendronate for up to 5 years. A per protocol analysis would be interesting given use of drug therapy including alendronate in 83 of 428 subjects in the placebo arm and cessation of alendronate in 63 of 321 (5mg) and 71 of 322 (10 mg) in the treatment arm. —ES
◆ Deane A, Constancio L, Fogelman I, Hampson G. The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis. BMC Musculoskelet Disord. 2007 Jan 10;8(1):3 [Epub ahead of print]
Do vitamin D and/or PTH levels influence the BMD response to bisphosphonates? Considering that at least 50% of osteoporosis patients still taking bisphosphonates after one year may have dropped their vitaminD/calcium supplements, the question is of importance. This small, observational study in 112 post-menopausal women receiving alendronate, risedronate or etidronate suggests that 4-yr BMD changes at the spine were unaffected by PTH levels and vitamin D status, whereas at the hip, no BMD gain was observed in the group with higher PTH levels, nor in those with 25OHD values below 70 nmol/L, i.e. the currently recommended threshold. Although not definitive, these results are intriguing. —SF
Reviews, perspectives and editorials◆ Berenson JR, Rajdev L, Broder M. Managing bone complications of solid tumors. Cancer Biol Ther. 2006 Sep;5(9):1086–9.
◆ Bischoff-Ferrari HA. How to select the doses of vitamin D in the management of osteoporosis. Osteoporos Int. 2006 Dec 7; [Epub ahead of print]
◆ Boyce BF, Xing L. Osteoclasts, no longer osteoblast slaves. Nat Med. 2006 Dec;12(12):1356–8.
◆ Cummings SR. A 55-year-old woman with osteopenia. JAMA. 2006 Dec 6;296(21):2601–10.
◆ Dunstan CR, Felsenberg D, Seibel MJ. Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol. 2007 Jan;4(1):42–55.
◆ Harrison RA, Siminoski K, Vethanayagam D, Majumdar SR. Osteoporosis-related kyphosis and impairments in pulmonary function: a systematic review. J Bone Miner Res. 2006 Dec 20; [Epub ahead of print]
◆ Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H. Vascular calcification and osteoporosis-from clinical observation towards molecular understanding. Osteoporos Int. 2006 Dec 7; [Epub ahead of print]
◆ Martin TJ, Seeman E. New mechanisms and targets in the treatment of bone fragility. Clin Sci (Lond). 2007 Feb;112(2):77–91.
◆ Mbalaviele G, Shin CS, Civitelli R. Cell-cell adhesion and signaling through cadherins: connecting bone cells in their microenvironment. J Bone Miner Res. 2006 Dec;21(12):1821–7.
◆ Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ. 2006 Dec 15; [Epub ahead of print]
◆ Poole KE, Compston JE. Osteoporosis and its management. BMJ. 2006 Dec 16;333(7581):1251–6.
◆ Schwartz GG, Skinner HG. Vitamin D status and cancer: new insights. Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):6–11.
◆ Seeman E. The periosteum-a surface for all seasons. Osteoporos Int. 2007 Feb;18(2):123–8.
◆ Shapiro IM, Srinivas V. Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment. Bone. 2006 Dec 6; [Epub ahead of print]
◆ Zhao Q, Shao J, Chen W, Li YP. Osteoclast differentiation and gene regulation. Front Biosci. 2007 Jan 1;12:2519–29.
Other studies of potential interest◆ Abdallah BM, Boissy P, Tan Q, Dahlgaard J, Traustadottir GA, Kupisiewicz K, Laborda J, Delaisse JM, Kassem M. DLK1/FA1 regulates the function of human bone marrow mesenchymal stem cells (HMSC) by modulating gene expression of pro-inflammatory cytokines and immuneresponse-related factors. J Biol Chem. 2006 Dec 19; [Epub ahead of print]
◆ Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2006 Dec 4; [Epub ahead of print]
◆ Burnett-Bowie SA, Mendoza N, Leder BZ. Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men. Bone. 2006 Dec 6; [Epub ahead of print]
◆ Ghosh-Choudhury N, Mandal CC, Ghosh Choudhury G. Statin-induced Ras activation integrates PI 3 kinase signal to AKT and MAPK for BMP-2 expression in osteoblast differentiation. J Biol Chem. 2006 Dec 19; [Epub ahead of print]
◆ Krejci P, Masri B, Salazar L, Farrington-Rock C, Prats H, Michels-Thompson L, Wilcox WR. Bisindolylmaleimide I suppresses FGF-mediated activation of ERK map kinase in chondrocytes by preventing SHP2 association with the FRS2 and GAB1 adaptor proteins. J Biol Chem. 2006 Dec 4; [Epub ahead of print]
◆ Kurihara N, Hiruma Y, Zhou H, Subler MA, Dempster DW, Singer FR, Reddy SV, Gruber HE, Windle JJ, Roodman GD. Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease. J Clin Invest. 2007 Jan 2;117(1):133–42.
◆ Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG. Site-specific K63-linked TRAF6 auto-ubiquitination is a critical determinant of IKK activation. J Biol Chem. 2006 Nov 29; [Epub ahead of print]
◆ Li QP, Qi XM, Pramanik R, Pohl NM, Loesch M, Chen G. Stress-induced c-Jun-dependent vitamin D receptor (VDR) activation dissects the non-classical VDR pathway from the classical VDR activity. J Biol Chem. 2007 Jan 19;282(3):1544–51.
◆ Lin YL, de Villiers WJ, Garvy BA, Post SR, Nagy TR, Safadi FF, Faugere MC, Wang G, Malluche HH, Williams JP. The effect of class A scavenger receptor (SR-A) deficiency in bone. J Biol Chem. 2006 Dec 13; [Epub ahead of print]
◆ Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S, Schwarz T, Penninger JM, Beissert S. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006 Dec;12(12):1372–9.
◆ Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832–8.
◆ Oganesian A, Au S, Horst JA, Holzhausen LC, Macy AJ, Pace JM, Bornstein P. The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function. J Biol Chem. 2006 Dec 15;281(50):38507–18.
◆ Panupinthu N, Zhao L, Possmayer F, Ke HZ, Sims SM, Dixon SJ. P2X7 nucleotide receptors mediate blebbing in osteoblasts through a pathway involving lysophosphatidic acid. J Biol Chem. 2006 Nov 29; [Epub ahead of print]
◆ Recker RR, Kendler D, Recknor CP, Rooney TW, Lewiecki EM, Utian WH, Cauley JA, Lorraine J, Qu Y, Kulkarni PM, Gaich CL, Wong M, Plouffe L Jr, Stock JL. Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone. 2006 Dec 18; [Epub ahead of print]
◆ Reinhold MI, Naski MC. Direct interactions of Runx2 and canonical Wnt signaling induce FGF18. J Biol Chem. 2006 Dec 11; [Epub ahead of print]
◆ Schilling AF, Mulhausen C, Lehmann W, Santer R, Schinke T, Rueger JM, Amling M. High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. Osteoporos Int. 2007 Jan 6; [Epub ahead of print]
◆ Vitarius JA, Sehayek E, Breslow JL. Identification of quantitative trait loci affecting body composition in a mouse intercross. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19860–5.
◆ Walters JR, Balesaria S, Khair U, Sangha S, Banks L, Berry JL. The effects of Vitamin D metabolites on expression of genes for calcium transporters in human duodenum. J Steroid Biochem Mol Biol. 2007 Jan 2; [Epub ahead of print]
◆ Wang S, Zhang C, Nordeen SK, Shapiro DJ. In vitro fluorescence anisotropy analysis of the interaction of full-length SRC1a with estrogen receptors alpha and beta supports an active displacement model for coregulator utilization. J Biol Chem. 2006 Nov 29; [Epub ahead of print]
◆ Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab. 2007 Jan 9; [Epub ahead of print]
◆ Wu L, Wu Y, Lin Y, Jing W, Nie X, Qiao J, Liu L, Tang W, Tian W. Osteogenic differentiation of adipose derived stem cells promoted by overexpression of osterix. Mol Cell Biochem. 2007 Jan 6; [Epub ahead of print]
◆ Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006 Dec 27;296(24):2947–53.
◆ Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow D, Lee B. Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19004–9.
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