BoneKEy-Osteovision | Not To Be Missed

Clinical and basic research papers: December 2002 selections



DOI:10.1138/2003080

Bone modeling and remodeling

◆ Li X, Udagawa N, Itoh K, Suda K, Murase Y, Nishihara T, Suda T, Takahashi N. p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Endocrinology. 2002 Aug;143(8):3105–13.

Recommended. —ES

◆ Takeuchi Y, Watanabe S, Ishii G, Takeda S, Nakayama K, Fukumoto S, Kaneta Y, Inoue D, Matsumoto T, Harigaya K, Fujita T. Interleukin-11 as a stimulatory factor for bone formation prevents bone loss with advancing age in mice. J Biol Chem. 2002 Dec 13;277(50):49011–8.

Several members of the GP130-linked IL-6 cytokine family increase osteoblast function. Here it is reported that targeting of IL11 to osteoblasts increases cortical and trabecular bone mass, prevents bone loss with aging, and increases osteoblast production in marrow cultures. —GJS

Epidemiology

◆ Feskanich D, Willett W, Colditz G. Walking and leisure-time activity and risk of hip fracture in postmenopausal women. JAMA. 2002 Nov 13;288(18):2300–6.

◆ Wang BW, Ramey DR, Schettler JD, Hubert HB, Fries JF. Postponed development of disability in elderly runners: a 13-year longitudinal study. Arch Intern Med. 2002 Nov 11;162(20):2285–94.

Is Exercise Really That Good? Feskanich et al. report that a history of exercise and even standing is associated with a reduced risk of hip fracture. Wang et al. suggest lower disability and longer life span for members of a runners’ club. Can bias be ruled out in these observational studies? My bias is that their study is biased by the type of individual who would join such a club. Nor do I intend on standing when I type. —ES

◆ Lemaitre RN, Heckbert SR, Psaty BM, Smith NL, Kaplan RC, Longstreth WT Jr. Hormone replacement therapy and associated risk of stroke in postmenopausal women. Arch Intern Med. 2002 Sep 23;162(17):1954–60.

Estrogen and Early Stroke: Neither ischemic or hemorrhagic stroke were associated with current use of HRT but the risks were increased 2-fold during the first 6 months of treatment. —ES

Genetics

◆ Bai X, Miao D, Panda D, Grady S, McKee MD, Goltzman D, Karaplis AC. Partial Rescue of the Hyp Phenotype by Osteoblast-Targeted PHEX (Phosphate-Regulating Gene with Homologies to Endopeptidases on the X Chromosome) Expression. Mol Endocrinol. 2002 DEC;16(12):2913–25.

Targeting the PHEX gene to osteoblasts with the Col1A1 promoter partially rescues Hyp mice from osteomalacia without affecting their hypophosphatemia. The rescue is more pronounced than in another recent publication, using the osteocalcin promoter for targeting (Liu et al.). These results suggest that the PHEX protease has a local function in bone that is separable from its putative systemic role to generate a phosphatonin, possibly FGF23. —GJS

◆ Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B, Hulin P, Benque-Blanchet F, Silve C, Grandchamp B, Friedlander G. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med. 2002 Sep 26;347(13):983–91.

Recommended. —ES

Pathophysiology

◆ Donohue MM, Demay MB. Rickets in VDR null mice is secondary to decreased apoptosis of hypertrophic chondrocytes. Endocrinology. 2002 Sep;143(9):3691–4.

Recommended. —ES

◆ McDougall KE, Perry MJ, Gibson RL, Bright JM, Colley SM, Hodgin JB, Smithies O, Tobias JH. Estrogen-induced osteogenesis in intact female mice lacking ERbeta. Am J Physiol Endocrinol Metab. 2002 Oct;283(4):E817–23.

Estrogen is Envelop Specific: ER beta deficit mice have increased cortical bone mass in these animals suggesting the inhibitory effect of E on periosteal apposition is mediated through this receptor. Endocortical apposition in response to E was unaffected. —ES

Physiology and metabolism

◆ Bonnelye E, Kung V, Laplace C, Galson DL, Aubin JE. Estrogen receptor-related receptor alpha impinges on the estrogen axis in bone: potential function in osteoporosis. Endocrinology. 2002 Sep;143(9):3658–70.

Recommended. —ES

◆ Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, Muenke M, Lian JB, Yang Y, Nuckolls GH, Stein GS, Liu PP. Cbfbeta interacts with Runx2 and has a critical role in bone development. Nat Genet. 2002 DEC;32(4):639–44.

◆ Yoshida CA, Furuichi T, Fujita T, Fukuyama R, Kanatani N, Kobayashi S, Satake M, Takada K, Komori T. Core-binding factor beta interacts with Runx2 and is required for skeletal development. Nat Genet. 2002 DEC;32(4):633–8.

◆ Miller J, Horner A, Stacy T, Lowrey C, Lian JB, Stein G, Nuckolls GH, Speck NA. The core-binding factor beta subunit is required for bone formation and hematopoietic maturation. Nat Genet. 2002 DEC;32(4):645–9.

These three back-to-back papers report evidence that CBF-beta, the cousin of runx2/cbfa1, has a role in bone development. Cbfb(-/-) is an early embryonic lethal and this previously precluded examining its role in bone. Yoshida et al. and Miller et al. rescued embryos by expressing cbfb in hematopoeitic tissue. Kundu et al. knocked in a hypomorphic cbfb-GFP allele. In all cases the phenotype resembles the cbfa1/runx2(-/-) phenotype, with essentially no mineralized skeleton in the rescued knockout mice and a milder phenotype in mice with a hypomorphic allele. In vitro, cbfb interacts with cbfa1/runx2 and enhances cbfa1/runx2-dependent transcription. Cbfa1/runx2 and cbf-beta are partners in cartilage and bone development. —GJS

◆ You J, Jacobs CR, Steinberg TH, Donahue HJ. P2Y purinoceptors are responsible for oscillatory fluid flow-induced intracellular calcium mobilization in osteoblastic cells. J Biol Chem. 2002 DEC 13;277(50):48724–9.

Candidates proposed to mediate the effects of mechanical stress on bone include the integrin-cytoskeleton-nuclear matrix structure, stretch-activated cation channels, the phospholipase C or phospholipase A pathways, NO, glutamate, osteocyte apoptosis, and G protein-mediated pathways. Here, it is shown that intracellular calcium mobilization in response to oscillatory fluid flow is mediated by purinergic receptors on the surface of MC3T3-E1 cells. —GJS

Treatment and drug effects

◆ Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz A, Dore RK, Correa-Rotter R, Papaioannou A, Cumming DC, Hodsman AB. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002 Oct;87(10):4528–35.

Anabolics Trumps Anti-Resorptives: Teriparatide for 14 months results in fewer non-vertebral fractures than alendronate and may increase vertebral area more than alendronate. —ES

◆ Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro M. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002 DEC 15;62(24):7284–90.

The pharmaceutical industry has evolved reasonably efficient methods to produce specific kinase inhibitors. This compound shows promise for patients with MEN2, sporadic medullary thyroid carcinoma and papillary thyroid carcinoma. —GJS

◆ Kousteni S, Chen JR, Bellido T, Han L, Ali AA, O'Brien CA, Plotkin L, Fu Q, Mancino AT, Wen Y, Vertino AM, Powers CC, Stewart SA, Ebert R, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science. 2002 Oct 25;298(5594):843–6.

Estren and Nongenotropic Pathways to Bone: This ligand of the estrogen receptor has no transcriptional activity and increases bone mass and strength in ovariectomized females and is as effective as dihydrotestosterone in gonadectomized males. Estren, like DHT and estradiol attenuated osteoblast apoptosis and stimulated osteoclast apoptosis, and prevented gonadectomy induced osteoblast apoptosis in vertebrae of male and female mice. In vivo, estren prevented bone loss and increased bone mass following gonadectomy above that found of estrogen (or DHT in gonadectomized males). There was no effect of estren on reproductive tissues. Not to be missed. —ES

◆ Sato M, Vahle J, Schmidt A, Westmore M, Smith S, Rowley E, Ma LY. Abnormal bone architecture and biomechanical properties with near-lifetime treatment of rats with PTH. Endocrinology. 2002 Sep;143(9):3230–42.

Less is More: Too much of many good things in life increase bone fragility, and life long PTH obliterates the marrow and increases bone fragility in long bones of rats. —ES

◆ Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson P, Tardif JC, Higginson L, Bittner V, Steffes M, Gordon DJ, Proschan M, Younes N, Verter JI. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002 Nov 20;288(19):2432–40.

Myths That Vitamins Won't Help But Can't Hurt: Coronary progression worsened with HRT, placebo and with antioxidant vitamins. Neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment. —ES


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