BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers: January 2003 selections
DOI:10.1138/2003081
Bone modeling and remodeling◆ Gowen LC, Petersen DN, Mansolf AL, Qi H, Stock JL, Tkalcevic GT, Simmons HA, Crawford DT, Chidsey-Frink KL, Ke HZ, McNeish JD, Brown TA. Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass. J Biol Chem. 2003 Jan 17;278(3):1998–2007.
This paper is important for two reasons. Knockout of OF45/MEPE identifies this matrix protein as a negative regulator of osteoblast function. It could act directly on osteoblasts or as part of an osteocyte-osteoblast pathway. But in addition, the OF45/MEPE knockout mouse has a normal serum phosphorus level, arguing strongly against the role proposed for MEPE as a phosphatonin. —GJS
◆ Hoff AO, Catala-Lehnen P, Thomas PM, Priemel M, Rueger JM, Nasonkin I, Bradley A, Hughes MR, Ordonez N, Cote GJ, Amling M, Gagel RF. Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene. J Clin Invest. 2002 Dec;110(12):1849–57.
Recommended. —ES
◆ Qiu S, Rao DS, Palnitkar S, Parfitt AM. Relationships between osteocyte density and bone formation rate in human cancellous bone. Bone. 2002 DEC;31(6):709–11.
Recommended. —ES
◆ Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002 DEC;3(6):889–901.
The transcription factor NFAT is activated by RANKL in bone marrow macrophages, via TRAF6 and c-Fos dependent pathways. RANKL also induces oscillatory calcium signals that activate calcineurin, leading to phosphorylation and nuclear transport of NFAT. NFAT acts as a transcriptional master switch for terminal differentiation of osteoclasts. The results describe a new and important signaling pathway for RANKL. —GJS
◆ Weitzmann MN, Roggia C, Toraldo G, Weitzmann L, Pacifici R. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest. 2002 DEC;110(11):1643–50.
Recommended. —ES
Epidemiology◆ The relationship between bone density and incident vertebral fracture in men and women. J Bone Miner Res. 2002 DEC;17(12):2214–21.
Among 3,461 men and women, the risk of incident vertebral fracture is two fold greater in women than in men but not after adjusting for differences in BMD. At a given age and spine bone density, the risk of incident vertebral fracture is similar in men and women. The authors suggest incident vertebral fractures are more common in women than men because at any age their spine BMD is lower. That is, a greater proportion of women than men have bone structure and architecture below a given level so at any time more of them are at risk for fracture following a given level of ‘minimal ‘trauma. What is the trauma? Is it an absolute or a function of the musculoskeletal mass of the individual so smaller persons are subjected to smaller loads? —ES
◆ Roy DK, Pye SR, Lunt M, O'Neill TW, Todd C, Raspe H, Reeve J, Silman AJ. Falls explain between-center differences in the incidence of limb fracture across Europe. Bone. 2002 DEC;31(6):712–7.
The study of fracture pathogenesis is the study of a ratio, load/strength; we ignore the numerator, we can't quantify it, and we don't understand the denominator. Among about 13,000 men and women variation in fall rates explained 6-24% of the between-center variation in fractures. —ES
Genetics◆ Cao L, Li W, Kim S, Brodie SG, Deng CX. Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform. Genes Dev. 2003 Jan 15;17(2):201–13.
What is the relationship between aging and cancer? Here, it is shown that knockin of a hypomorphic allele of the breast cancer susceptibility gene Brca1 produces premature aging in male mice, including severe osteoporosis. As do certain mutations of p53, these findings indicate a fundamental relationship between cell aging and tumor suppression. Osteoporosis may be one price we pay for tumor suppression. —GJS
Pathophysiology◆ Kifor O, Moore FD Jr, Delaney M, Garber J, Hendy GN, Butters R, Gao P, Cantor TL, Kifor I, Brown EM, Wysolmerski J. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab. 2003 Jan;88(1):60–72.
Graves disease is the cardinal endocrine disorder produced by stimulatory antibodies. The finding of PTH-dependent hypercalcemia in patients with autoimmune disorders led to the identification of antibodies that stimulate the parathyroid calcium-sensing receptor, thereby producing a syndrome that mimics familial hypocalciuric hypercalcemia. —GJS
◆ Redlich K, Hayer S, Ricci R, David JP, Tohidast-Akrad M, Kollias G, Steiner G, Smolen JS, Wagner EF, Schett G. Osteoclasts are essential for TNF-alpha-mediated joint destruction. J Clin Invest. 2002 Nov;110(10):1419–27.
Redlich et al. report the results of a beautifully designed study crossing transgenic mice that express human TNF and develop destructive arthritis with osteopetrotic, c-fos-deficient mice lacking osteoclasts. Arthritis and joint destruction is found without bone destruction. Could bisphosphonates become an integral part of management of inflammatory arthritis? —ES
Physiology and metabolism◆ Cornish J, Callon KE, Bava U, Lin C, Naot D, Hill BL, Grey AB, Broom N, Myers DE, Nicholson GC, Reid IR. Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J Endocrinol. 2002 Nov;175(2):405–15.
Recommended. —ES
◆ van der Eerden BC, Emons J, Ahmed S, van Essen HW, Lowik CW, Wit JM, Karperien M. Evidence for genomic and nongenomic actions of estrogen in growth plate regulation in female and male rats at the onset of sexual maturation. J Endocrinol. 2002 Nov;175(2):277–88.
Recommended. —ES
◆ Kratochwil K, Galceran J, Tontsch S, Roth W, Grosschedl R. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes Dev. 2002 DEC 15;16(24):3173–85.
LEF1 mediates gene transcription in the classical pathway for Wnt action. Mice without LEF1 do not develop teeth, hair, mammary glands or vibrissia. The effect of LEF1 deficiency in the epithelium is nonautonomous, occurring in the underlying mesenchyme. Here it is shown that FGF4 is a direct transcriptional target for LEF1 and that the tooth phenotype of LEF1(-/-) mice can be rescued by FGF4. FGF4 relays a LEF1-dependent Wnt signal to a cascade of other events that are part of extensive epithelial-mesenchymal interactions. —GJS
◆ Sukhodolets KE, Hickman AB, Agarwal SK, Sukhodolets MV, Obungu VH, Novotny EA, Crabtree JS, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ. The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene. Mol Cell Biol. 2003 Jan;23(2):493–509.
Cloning of the MEN1 tumor suppression gene identified the protein menin, the function of which is unknown. Menin is known to interact in vitro with SMAD2, junD, NF B, and other proteins. This paper reports the identification of a subunit of RPA, a protein involved in DNA replication, as a binding partner for menin. Menin colocalizes with RPA within the nucleus. In many cases MEN1 mutations in menin block binding to RPA2. These findings make RPA a strong candidate as one of the physiologically important dancing partners of menin. —GJS
Treatment and drug effects◆ Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, Elstein M, Kay C, Seif M, Buckley H. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet. 2002 DEC 21-28;360(9350):2001–8.
Observational studies purporting cardio-protection are usually conducted in women receiving estrogen alone. Prospective studies reporting no cardio-protection like HERS and the WHI involved the use of combined therapy. Is the difference the progestin? Cherry et al report that, in a randomized, blinded, placebo controlled study, estrogen alone failed to protect from re-infarction. Although the study may be under powered as it involved only about 1,000 patients studied for 2 years, it fails to support the notion that estrogen alone may be protective. The second part of the WHI study is awaited with interest. —ES
◆ Fukunaga M, Kushida K, Kishimoto H, Shiraki M, Taketani Y, Minaguchi H, Inoue T, Morita R, Morii H, Yamamoto K, Ohashi Y, Orimo H. A comparison of the effect of risedronate and etidronate on lumbar bone mineral density in Japanese patients with osteoporosis: a randomized controlled trial. Osteoporos Int. 2002 DEC;13(12):971–9.
Recommended. —ES
◆ Gallwitz WE, Guise TA, Mundy GR. Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo. J Clin Invest. 2002 Nov;110(10):1559–72.; Comment in J Clin Invest: Martin TJ. Manipulating the environment of cancer cells in bone: a novel therapeutic approach. J Clin Invest. 2002 Nov;110(10):1399–401.
A screen of anticancer drugs identified these nucleotide analogs as drugs that block the secretion of PTHrP in vitro. They were then shown to inhibit osteoclastic metastases and improve survival in a standard animal model. —GJS
◆ Reginster JY, Deroisy R, Dougados M, Jupsin I, Colette J, Roux C. Related Articles, Links Prevention of early postmenopausal bone loss by strontium ranelate: the randomized, two-year, double-masked, dose-ranging, placebo-controlled PREVOS trial. Osteoporos Int. 2002 DEC;13(12):925–31.
Recommended. — ES
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