BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers – April 2005 selections
DOI:10.1138/20050159
Bone modeling and remodeling◆ Murshed M, Harmey D, Millan JL, McKee MD, Karsenty G. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev. 2005 May 1;19(9):1093–104.
Why is mineralization of the extracellular matrix normally unique to bone, teeth, and hypertrophic cartilage? This paper argues from a series of genetic and in vitro experiments that the simultaneous presence of three things is both necessary and sufficient for mineralization: an adequate concentration of phosphate; cellular expression of type I collagen, the substrate for mineralization; and the enzyme alkaline phosphatase, which serves to remove pyrophosphate, an inhibitor of mineralization. Ectopic expression of alkaline phosphatase is sufficient to mineralize the matrix of fibroblasts that express type I collagen. —GJS
◆ Yamashita M, Ying SX, Zhang GM, Li C, Cheng SY, Deng CX, Zhang YE. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell. 2005 Apr 8;121(1):101–13.
Smurf1 is a ubiquitin ligase that targets for destruction SMADs in the BMP signaling pathway. Smurf1(-/-) mice have increased osteoblast function and bone mass, but the primary target of Smurf1 in osteoblasts seems not to be a SMAD. Instead, the phosphorylated form of the protein kinase MEK kinase2 is directly bound by Smurf1 and targeted for degradation. MEK kinase2 is upstream of Jun-kinase and thereby regulates the transcription complex AP-1. —GJS
Pathophysiology◆ Wada T, Nakashima T, Oliveira-dos-Santos AJ, Gasser J, Hara H, Schett G, Penninger JM. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med. 2005 Apr;11(4):394–9.
Gab2 is a scaffolding protein that binds to receptor complexes, often via Grb; it is a target for phosphorylation and thereafter assembles other signaling molecules. The authors observed mild osteopetrosis in Gab2(-/-) mice and found decreased osteoclast numbers. Unexpectedly, Gab2 seems to be downstream of RANK: RANKL-induced osteoclastogenesis is impaired in Gab2(-/-) macrophages, and Gab2 associates with RANK and is phosphorylated upon exposure to RANKL. Gab2(-/-) osteoclasts have impaired signaling in some of the pathways downstream of RANK (e.g., JNK, AKT, and IκBα), but not all of them — phosphorylation of p38 and induction of NFAT are unaffected. It is not clear how Gab2 binds to RANK (e.g., does binding involve tumor necrosis factor receptor-associated factors?), how it is phosphorylated, or how it interacts with downstream signaling pathways. —GJS
Physiology and metabolism◆ Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med. 2005 May 12;352(19):1959-66. Canalis E. The fate of circulating osteoblasts. N Engl J Med. 2005 May 12;352(19):2014–6.
Osteoblast-lineage cells have previously been found in bone marrow and peripheral blood, but this report shows that the recovery of nonadherent cells with an osteoblast phenotype from peripheral blood is about 106-fold greater than the previously reported recovery of adherent cells — although it is difficult to ascertain the absolute number of cells from the report. The number of circulating osteoblast-lineage cells is markedly increased in two states of high bone turnover, adolescence and fracture. Where do these cells come from? What is their fate? —GJS
Treatment and drug effects◆ Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005 May 11;293(18):2257–64.
The epidemiologist Alvin Feinstein once observed that meta-analysis is to analysis as metaphysics is to physics. This meta-analysis, however, arrives at an important conclusion: a vitamin D supplement of at least 800 IU is required for prevention of fractures. It does so by pooling data on treatment in nursing homes and the community: Is this legitimate? And useful as it is, the conclusion is immediately challenged by a clinical trial that we also note this month (Lancet May 2005; 365(9471):1621–8.) —GJS
◆ Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, Anderson FH, Cooper C, Francis RM, Donaldson C, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA; RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005 May 7;365(9471):1621–8.
Current data suggest that supplementation of elderly persons with vitamin D (800 IU) can prevent fractures (see Bischoff–Ferrari JAMA May 2005; 293(18): 2257–64, noted elsewhere in this feature, and a recent review by Dawson-Hughes). In this study, 5292 people aged 70 years or older with a low-trauma fracture were randomly assigned vitamin D3 (800 IU), calcium (1000 mg), the combination, or placebo. After at least 24 months of followup the incidence of fractures in the treatment groups was not different from placebo. Only 54.5% of patients were still taking their medication at 24 months, and the mean 25OHD level achieved with supplements (in a small subset of subjects) was lower than in previous studies. The final word is still out on vitamin D supplementation to prevent fractures. —GJS
◆ Kaufman JM, Orwoll E, Goemaere S, San Martin J, Hossain A, Dalsky GP, Lindsay R, Mitlak BH. Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int. 2005 May;16(5):510–6.
Stopping PTH is associated with bone loss. Antiresorptives prevent the decline. Of 279 men, 11.7% assigned to placebo, 5.4% treated with teriparatide (20 μg), and 6.0% treated with teriparatide (40 μg) had vertebral fractures. In treatment groups combined vs. placebo, risk of vertebral fracture was reduced by 51% (p = 0.07). The incidence of moderate or severe fractures was reduced by 83% (p = 0.01). —ES
◆ McCombs JS, Thiebaud P, McLaughlin-Miley C, Shi J. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas. 2004 Jul 15;48(3):271–87.
There is no point in effective therapy if compliance is poor. In 58,109 patients with osteoporosis initiating therapy, one-year compliance rates were less than 25%. Mean duration of therapy was 221 days for raloxifene, 245 days for bisphosphonates, 262 for estrogen-only, and 292 days for estrogen plus progestin. Poor compliance was associated with higher fracture rates at the hip and use of more physicians and outpatient services. General patient-, drug-, and doctor-related factors causing poor compliance are not well defined, nor are methods of improving compliance. However, whether higher morbidity or mortality rates in poor compliers is actually caused by omission of therapy is uncertain, as poor compliance with placebo is associated with twice the mortality of compliers with placebo (Lancet 1990;336:542, NEJM 1980;303:1038) —ES
◆ Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM; Fracture Intervention Trial Research Group. Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005 Mar;80(3):343–9.
One-half of all fractures in the community come from women with osteopenia or normal BMD. Quandt et al. inferred that alendronate reduces vertebral fracture risk in patients with femoral neck (FN) osteopenia. There was a 60% reduction in clinical vertebral fractures and a 43% reduction in radiographic vertebral fractures in a combined group of patients with FN osteopenia with a prevalent fracture from the Fracture Intervention Trial 1 (FIT 1) and FN osteopenia without a prevalent fracture from FIT 2. However, there was risk reduction in patients with FN osteopenia alone (i.e., without a prevalent fracture) (95% confidence intervals; 0.16-1.17 for clinical and 0.38-1.10 for radiographic vertebral fractures). It is impossible to determine whether the women with spinal osteopenia alone had a fracture risk reduction because spinal osteopenia may be osteoporosis with osteophytes. Post hoc pooling and statistics are not substitutes for study design. —ES
Reviews, perspectives, and editorials◆ Ariyoshi W, Takahashi T, Kanno T, Ichimiya H, Takano H, Koseki T, Nishihara T. Mechanisms involved in enhancement of osteoclast formation and function by low molecular weight hyaluronic acid. J Biol Chem. 2005 May 13;280(19):18967–72.
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◆ Coleman RE. Bisphosphonates in breast cancer. Ann Oncol. 2005 May;16(5):687–95.
◆ Compston J. Prevention of vertebral fractures by strontium ranelate in postmenopausal women with osteoporosis. Osteoporos Int. 2005 Jan;16 Suppl 1:S4–6
◆ Delmas PD. Clinical effects of strontium ranelate in women with postmenopausal osteoporosis. Osteoporos Int. 2005 Jan;16 Suppl 1:S16–9.
◆ Delmas PD, Rizzoli R, Cooper C, Reginster JY. Treatment of patients with postmenopausal osteoporosis is worthwhile. The position of the International Osteoporosis Foundation. Osteoporos Int. 2005 Jan;16(1):1–5.
◆ Egermann M, Schneider E, Evans CH, Baltzer AW. The potential of gene therapy for fracture healing in osteoporosis. Osteoporos Int. 2005 Mar;16 Suppl 2:S120–8
◆ Elmquist JK, Strewler GJ. Physiology: do neural signals remodel bone. Nature. 2005 Mar 24;434(7032):447–8.
◆ Faulkner KG. The tale of the T-score: review and perspective. Osteoporos Int. 2005 Apr;16(4):347–52.
◆ Gainford MC, Dranitsaris G, Clemons M. Recent developments in bisphosphonates for patients with metastatic breast cancer. BMJ. 2005 Apr 2;330(7494):769–73.
◆ Lester J, Dodwell D, McCloskey E, Coleman R. The causes and treatment of bone loss associated with carcinoma of the breast. Cancer Treat Rev. 2005 Apr;31(2):115–42.
◆ Maalouf NM, Shane E. Osteoporosis after solid organ transplantation. J Clin Endocrinol Metab. 2005 Apr;90(4):2456–65.
◆ Marie PJ. Strontium ranelate: a novel mode of action optimizing bone formation and resorption. Osteoporos Int. 2005 Jan;16 Suppl 1:S7–10.
◆ Pogoda P, Priemel M, Rueger JM, Amling M. Bone remodeling: new aspects of a key process that controls skeletal maintenance and repair. Osteoporos Int. 2005 Mar;16 Suppl 2:S18–24
◆ Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res. 2005 Feb;20(2):177–84.
◆ Saxon LK, Turner CH. Estrogen receptor beta: the antimechanostat. Bone. 2005 Feb;36(2):185–92.
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◆ Strewler GJ. A 64-year-old woman with primary hyperparathyroidism. JAMA. 2005 Apr 13;293(14):1772–9.
◆ Teitelbaum SL. Osteoporosis and integrins. J Clin Endocrinol Metab. 2005 Apr;90(4):2466–8.
Other basic research studies of potential interest◆ Bai XC, Lu D, Liu AL, Zhang ZM, Li XM, Zou ZP, Zeng WS, Cheng BL, Luo SQ. Reactive oxygen species stimulates receptor activator of NF-kappaB ligand expression in osteoblast. J Biol Chem. 2005 Apr 29;280(17):17497–506.
◆ Cabral WA, Makareeva E, Colige A, Letocha AD, Ty JM, Yeowell HN, Pals G, Leikin S, Marini JC. Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. J Biol Chem. 2005 May 13;280(19):19259–69.
◆ de Beur SM. Tumoral calcinosis: a look into the metabolic mirror of phosphate homeostasis. J Clin Endocrinol Metab. 2005 Apr;90(4):2469–71.
◆ Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY, Lian JB, Stein JL, Stein GS, van Wijnen AJ. The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts. J Biol Chem. 2005 May 27;280(21):20274–85.
◆ Healy KD, Vanhooke JL, Prahl JM, DeLuca HF. Parathyroid hormone decreases renal vitamin D receptor expression in vivo. Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4724–8.
◆ Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, Deng L, Clemens TL, Williams BO. Essential Role of {beta}-Catenin in Postnatal Bone Acquisition. J Biol Chem. 2005 Jun 3;280(22):21162–8.
◆ Ichikawa S, Lyles KW, Econs MJ. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive. J Clin Endocrinol Metab. 2005 Apr;90(4):2420–3.
◆ Keselowsky BG, Collard DM, Garcia AJ. Integrin binding specificity regulates biomaterial surface chemistry effects on cell differentiation. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5953–7.
◆ Kim MS, Day CJ, Morrison NA. MCP-1 is induced by receptor activator of nuclear factor-{kappa}B ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation. J Biol Chem. 2005 Apr 22;280(16):16163–9.
◆ Korcok J, Raimundo LN, Du X, Sims SM, Dixon SJ. P2Y6 nucleotide receptors activate NF-kappaB and increase survival of osteoclasts. J Biol Chem. 2005 Apr 29;280(17):16909–15.
◆ Larsson T, Yu X, Davis SI, Draman MS, Mooney SD, Cullen MJ, White KE. A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocrinol Metab. 2005 Apr;90(4):2424–7.
◆ Mansukhani A, Ambrosetti D, Holmes G, Cornivelli L, Basilico C. Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation. J Cell Biol. 2005 Mar 28;168(7):1065–76.
◆ Niedermaier M, Schwabe GC, Fees S, Helmrich A, Brieske N, Seemann P, Hecht J, Seitz V, Stricker S, Leschik G, Schrock E, Selby PB, Mundlos S. An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression. J Clin Invest. 2005 Apr;115(4):900–9.
◆ Qiao B, Padilla SR, Benya PD. Transforming growth factor (TGF)-beta-activated kinase 1 mimics and mediates TGF-beta-induced stimulation of type II collagen synthesis in chondrocytes independent of Col2a1 transcription and Smad3 signaling. J Biol Chem. 2005 Apr 29;280(17):17562–71.
◆ Sakamoto A, Chen M, Nakamura T, Xie T, Karsenty G, Weinstein LS. Deficiency of the G-protein {alpha}-Subunit Gs{alpha} in Osteoblasts Leads to Differential Effects on Trabecular and Cortical Bone. J Biol Chem. 2005 Jun 3;280(22):21369–21375.
◆ Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, Yamada Y, Costantini F, Wakisaka S, Pacifici M, Iwamoto M, Enomoto-Iwamoto M. Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem. 2005 May 13;280(19):19185–95.
◆ Venken K, Boonen S, Van Herck E, Vandenput L, Kumar N, Sitruk-Ware R, Sundaram K, Bouillon R, Vanderschueren D. Bone and muscle protective potential of the prostate-sparing synthetic androgen 7alpha-methyl-19-nortestosterone: Evidence from the aged orchidectomized male rat model. Bone. 2005 Apr;36(4):663–70.
◆ Vertino AM, Bula CM, Chen JR, Almeida M, Han L, Bellido T, Kousteni S, Norman AW, Manolagas SC. Nongenotropic, anti-apoptotic signaling of 1alpha,25(OH)2-vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes. Mediation by Src, phosphatidylinositol 3-, and JNK kinases. J Biol Chem. 2005 Apr 8;280(14):14130–7.
◆ Xu G, Nie H, Li N, Zheng W, Zhang D, Feng G, Ni L, Xu R, Hong J, Zhang JZ. Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J Clin Invest. 2005 Apr;115(4):1060–7.
Other clinical research studies of potential interest◆ Acheson LS. Bone density and the risk of fractures: should treatment thresholds vary by race. JAMA. 2005 May 4;293(17):2151–4.
◆ Ammann P. Strontium ranelate: a novel mode of action leading to renewed bone quality. Osteoporos Int. 2005 Jan;16 Suppl 1:S11–5.
◆ Cauley JA, Lui LY, Ensrud KE, Zmuda JM, Stone KL, Hochberg MC, Cummings SR. Bone mineral density and the risk of incident nonspinal fractures in black and white women. JAMA. 2005 May 4;293(17):2102–8.
◆ Orsini LS, Rousculp MD, Long SR, Wang S. Health care utilization and expenditures in the United States: a study of osteoporosis-related fractures. Osteoporos Int. 2005 Apr;16(4):359–71.
◆ Papapoulos SE, Quandt SA, Liberman UA, Hochberg MC, Thompson DE. Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporos Int. 2005 May;16(5):468–474.
◆ Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005 May;90(5):2816–22.
◆ Ruimerman R, Hilbers P, van Rietbergen B, Huiskes R. A theoretical framework for strain-related trabecular bone maintenance and adaptation. J Biomech. 2005 Apr;38(4):931–41.
◆ Sambrook P. Vitamin D and fractures: quo vadis. Lancet. 2005 May 7;365(9471):1599–600.
◆ Schousboe JT, Nyman JA, Kane RL, Ensrud KE. Cost-effectiveness of alendronate therapy for osteopenic postmenopausal women. Ann Intern Med. 2005 May 3;142(9):734–41.
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