BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers – February 2005 selections
DOI:10.1138/20050152
Bone modeling and remodeling◆ Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, Macdougald OA. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3324–9.
Expression of Wnt10b in marrow adipocytes, using the FABP4 promoter, reduces marrow adiposity and dramatically increases bone mass. The effects of ovariectomy on bone mass are markedly blunted by transgene expression. Conversely, Wnt10b-null mice have osteopenia. Wnt10b expression inhibits peroxisome proliferator-activated receptor γ(PPARγ), potentially redirecting mesenchymal cells into the osteoblast lineage, and reduces fat mass, thereby decreasing leptin levels; as well as signaling directly in osteoblasts through the canonical wnt pathway.—GJS
◆ Harrison JR, Huang YF, Wilson KA, Kelly PL, Adams DJ, Gronowicz GA, Clark SH. Col1a1 Promoter-targeted Expression of p20 CCAAT Enhancer-binding Protein {beta} (C/EBP{beta}), a Truncated C/EBP{beta} Isoform, Causes Osteopenia in Transgenic Mice. J Biol Chem. 2005 Mar 4;280(9):8117–24.
C/EBP transcription factors regulate adipocyte differentiation. Osteoblasts and adipocytes share a common pluripotent progenitor in marrow. C/EBP transcription factors were disrupted in osteoblast lineage cells by overexpressing a dominant negative C/EBP isoform. All transgenic lines showed evidence of osteopenia and decreased mineral apposition and bone formation rates, reduced COL1A1 and osteocalcin mRNA levels, and increased BSP mRNA, consistent with an inhibition of terminal osteoblast differentiation. C/EBP transcription factors may be important determinants of osteoblast function and bone mass. —ES
Pathophysiology◆ Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R. Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab. 2005 Feb;90(2):1012–20.
Conditioned medium from two tumors associated with oncogenic osteomalacia has high levels of fibroblast growth factor 7 (FGF7) and much lower levels of FGF23. Inhibition of phosphate transport by conditioned medium is blocked by neutralizing antibodies to FGF7. Thus, FGF7 may be a second phosphaturic member of the FGF family. Assays of FGF7 in blood will be necessary to prove the point. —GJS
◆ David JP, Mehic D, Bakiri L, Schilling AF, Mandic V, Priemel M, Idarraga MH, Reschke MO, Hoffmann O, Amling M, Wagner EF. Essential role of RSK2 in c-Fos-dependent osteosarcoma development. J Clin Invest. 2005 March 1;115(3):664–672.
The protein kinase Rsk2 was recently shown to be required for osteoblast function (Yang, X. et al. Cell. 2004 117: 387-398). Here it is shown that Rsk2-null mice have osteopenia and mild osteomalacia. Phex is absent from cortical bone, but phosphate-wasting does not occur. Osteosarcomas are induced in Rsk2(-/-) mice by a c-fos transgene, but grow very slowly. Rsk2 affects osteoblast matrix synthesis, mineralization, and osteosarcoma formation. —GJS
Treatment and drug effects◆ Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology. 2005 Mar;146(3):1226–35.
The adipocyte receptor PPARγ directs mesenchymal precursors preferentially into the adipocyte pathway. Treatment of Swiss Webster mice with the PPARγ agonist rosiglitizone reduces bone mass. This is associated with reductions in bone formation rate and wall thickness, without effects on osteoblast apoptosis. Negative rosiglitizone effects on osteoblasts have also been reported by others (Rzonca SO et al. Endocrinology 2004 145: 401–406; Soroceanu et al. J Endocrinol 2004 183: 203–216). Does diabetes treatment with thiazolidinediones have adverse effects on bone? —GJS
◆ Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005 Mar;90(3):1294–301.
Antiresorptives reduce the remodeling rate, progression of cortical thinning and porosity, trabecular thinning, and loss of connectivity. The drugs allow more time for secondary mineralization, and thus, increased tissue mineral density. If treatment is prolonged, there is concern that tissue mineral density and homogeneity may increase “too much”, which may predispose to micro-damage production and progression, whereas reduced targeted remodeling may reduce removal of microdamage. There is evidence that greater remodeling suppression is associated with more microdamage; however evidence that reduced remodeling increases tissue mineral density which increases microdamage that leads to loss of antifracture efficacy, is not available. In this study, nine patients sustained spontaneous nonspinal fracture while receiving alendronate; while six of the patients had delayed or absent fracture healing. Histomorphometry showed suppressed bone formation. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. Whether there is a causal relationship between fracture and alendronate therapy is not proven in this study. —ES
◆ Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S, Kagan R, Chen E, Petruschke RA, Thompson DE, de Papp AE; Fosamax Actonel Comparison Trial Investigators. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res. 2005 Jan;20(1):141–51.
Greater suppression of remodeling, and thus greater gains in BMD, were reported with alendronate than risedronate. The unstated (but implied) inference is that the 1% to 2% difference in BMD between the drugs or the difference in remodeling suppression (50% vs. 35%, respectively) translates into fewer fracture events. If one drug is more “potent” than another, however, does this drug more greatly reduce activation frequency, reduce the volume of bone resorbed, increase the volume of bone deposited in each basic multicellular unit, or more greatly increase the degree of secondary mineralization? From these mechanistic differences, does alendronate more greatly reduce the appearance of cortical porosity; reduce the rate of progression of cortical thinning, trabecular thinning, and loss of connectivity; or more greatly reduce the removal of microdamage and increase microdamage production? Some features will be advantageous, others may be disadvantageous. It is therefore not possible to imply inferences about the relative antifracture efficacy of drugs, unless there is evidence of how many fewer patients need to be treated with one drug than another. Read more —ES
◆ Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA. 2005 Mar 2;293(9):1082–8.
Previous studies have shown a positive correlation between hip fracture and plasma homocysteine levels (N Engl J Med. 2004;350: 2033–41; N Engl J Med. 2004;350: 2042–49). Stroke patients are at high risk of hip fracture. Japanese patients with stroke (n = 628) were randomized to placebo or treatment with folic acid and mecobalamin to reduce homocysteine levels. Their homocysteine levels were high and fell with treatment. During two years of follow-up, 10 treated patients had a hip fracture, compared with 42 placebo-treated patients (adjusted relative risk, 0.20; 95% confidence interval, 0.08–0.50). —GJS
Reviews, perspectives, and editorials◆ Bielesz B, Klaushofer K, Oberbauer R. Renal phosphate loss in hereditary and acquired disorders of bone mineralization. Bone. 2004 Dec;35(6):1229–39.
◆ Bisello A, Horwitz MJ, Stewart AF. Parathyroid hormone-related protein: an essential physiological regulator of adult bone mass. Endocrinology. 2004 Aug;145(8):3551–3.
◆ Carter DR, Beaupre GS, Wong M, Smith RL, Andriacchi TP, Schurman DJ. The mechanobiology of articular cartilage development and degeneration. Clin Orthop Relat Res. 2004 Oct;(427 Suppl):S69–77
◆ Chien KR, Karsenty G. Longevity and lineages: toward the integrative biology of degenerative diseases in heart, muscle, and bone. Cell. 2005 Feb 25;120(4):533–44.
◆ Cohen A, Sambrook P, Shane E. Management of bone loss after organ transplantation. J Bone Miner Res. 2004 Dec;19(12):1919–32.
◆ Gennari L, Nuti R, Bilezikian JP. Aromatase activity and bone homeostasis in men. J Clin Endocrinol Metab. 2004 Dec;89(12):5898–907.
◆ Goldring MB, Berenbaum F. The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide. Clin Orthop Relat Res. 2004 Oct;(427 Suppl):S37–46
◆ Goldring SR, Goldring MB. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthop Relat Res. 2004 Oct;(427 Suppl):S27–36
◆ Jackman RW, Kandarian SC. The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol. 2004 Oct;287(4): C834–43
◆ Johnson ML, Harnish K, Nusse R, Van Hul W. LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res. 2004 Nov;19(11):1749–57.
◆ Kobayashi T, Kronenberg H. Minireview: transcriptional regulation in development of bone. Endocrinology. 2005 Mar;146(3):1012–7.
◆ Leung KC, Johannsson G, Leong GM, Ho KK. Estrogen regulation of growth hormone action. Endocr Rev. 2004 Oct;25(5):693–721.
◆ McLachlan RI, Allan CA. Defining the prevalence and incidence of androgen deficiency in aging men: where are the goal posts. J Clin Endocrinol Metab. 2004 Dec;89(12):5916–9.
◆ Mirza FS, Prestwood KM. Bone health and aging: implications for menopause. Endocrinol Metab Clin North Am. 2004 Dec;33(4):741–59.
◆ Peterson HB, Thacker SB, Corso PS, Marchbanks PA, Koplan JP. Hormone therapy: making decisions in the face of uncertainty. Arch Intern Med. 2004 Nov 22;164(21):2308–12.
◆ Reed SD, Newton KM, Lacroix AZ. Indications for hormone therapy: the post-Women's Health Initiative era. Endocrinol Metab Clin North Am. 2004 Dec;33(4):691–715.
◆ Rogers MJ. From molds and macrophages to mevalonate: a decade of progress in understanding the molecular mode of action of bisphosphonates. Calcif Tissue Int. 2004 Dec;75(6):451–61.
◆ Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK. Aging in rhesus monkeys: relevance to human health interventions. Science. 2004 Sep 3;305(5689):1423–6.
◆ Sharp L, Cardy AH, Cotton SC, Little J. CYP17 gene polymorphisms: prevalence and associations with hormone levels and related factors. a HuGE review. Am J Epidemiol. 2004 Oct 15;160(8):729–40.
◆ Simkin PA. Hydraulically loaded trabeculae may serve as springs within the normal femoral head. Arthritis Rheum. 2004 Oct;50(10):3068–75.
◆ Swerdloff RS, Wang C. Androgens and the ageing male. Best Pract Res Clin Endocrinol Metab. 2004 Sep;18(3):349–62.
Other studies of potential interest◆ Beaulieu V, Da Silva N, Pastor-Soler N, Brown CR, Smith PJ, Brown D, Breton S. Modulation of the Actin Cytoskeleton via Gelsolin Regulates Vacuolar H+-ATPase Recycling. J Biol Chem. 2005 Mar 4;280(9):8452–63.
◆ Colnot C, de la Fuente L, Huang S, Hu D, Lu C, St-Jacques B, Helms JA. Indian hedgehog synchronizes skeletal angiogenesis and perichondrial maturation with cartilage development. Development. 2005 Mar;132(5):1057–67.
◆ Corey E, Brown LG, Kiefer JA, Quinn JE, Pitts TE, Blair JM, Vessella RL. Osteoprotegerin in prostate cancer bone metastasis. Cancer Res. 2005 Mar 1;65(5):1710–8.
◆ Furumatsu T, Tsuda M, Taniguchi N, Tajima Y, Asahara H. Smad3 Induces Chondrogenesis through the Activation of SOX9 via CREB-binding Protein/p300 Recruitment. J Biol Chem. 2005 Mar 4;280(9):8343–50.
◆ Ikeda R, Yoshida K, Tsukahara S, Sakamoto Y, Tanaka H, Furukawa K, Inoue I. The Promyelotic Leukemia Zinc Finger Promotes Osteoblastic Differentiation of Human Mesenchymal Stem Cells as an Upstream Regulator of CBFA1. J Biol Chem. 2005 Mar 4;280(9):8523–30.
◆ Kawakami Y, Tsuda M, Takahashi S, Taniguchi N, Esteban CR, Zemmyo M, Furumatsu T, Lotz M, Belmonte JC, Asahara H. Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2414–9.
◆ Khundmiri SJ, Dean WL, McLeish KR, Lederer ED. Parathyroid Hormone-mediated Regulation of Na+-K+-ATPase Requires ERK-dependent Translocation of Protein Kinase C{alpha}. J Biol Chem. 2005 Mar 11;280(10):8705–13.
◆ Kizawa H, Kou I, Iida A, Sudo A, Miyamoto Y, Fukuda A, Mabuchi A, Kotani A, Kawakami A, Yamamoto S, Uchida A, Nakamura K, Notoya K, Nakamura Y, Ikegawa S. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet. 2005 Feb;37(2):138–44.
◆ Plotkin LI, Aguirre JI, Kousteni S, Manolagas SC, Bellido T. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J Biol Chem. 2005 Feb 25;280(8):7317–25.
◆ Ye L, Mishina Y, Chen D, Huang H, Dallas SL, Dallas MR, Sivakumar P, Kunieda T, Tsutsui TW, Boskey A, Bonewald LF, Feng JQ. Dmp1-deficient mice display severe defects in cartilage formation responsible for a chondrodysplasia-like phenotype. J Biol Chem. 2005 Feb 18;280(7):6197–203.
◆ Zannettino AC, Farrugia AN, Kortesidis A, Manavis J, To LB, Martin SK, Diamond P, Tamamura H, Lapidot T, Fujii N, Gronthos S. Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res. 2005 Mar 1;65(5):1700–9.
◆ Zayzafoon M, Fulzele K, McDonald JM. Calmodulin and calmodulin-dependent kinase IIalpha regulate osteoblast differentiation by controlling c-fos expression. J Biol Chem. 2005 Feb 25;280(8):7049–59.
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