BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers: June 2003 selections
DOI:10.1138/2003097
Bone modeling and remodeling◆ Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK. Bone loss and bone size after menopause. N Engl J Med. 2003 Jul 24;349(4):327–34.
What is new is the prospective documentation of increased periosteal apposition after menopause. What is puzzling is finding cortical thickness not reduced 15 years later, only displaced further from the neutral axis. This means periosteal apposition must be as great as the extent of endocortical resorption.
◆ Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, Thesleff I, Itoh N. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem. 2003 Jun 27;278(26):24113–7.
Sclerostin mutations cause the osteosclerotic disorders sclerostosis and van Buchem disease. The structure of sclerostin has a cysteine knot motif similar to BMP antagonists of the Cerberus/Dan family. Here it is shown directly that sclerostin binds to and inhibits the effects of BMP6 and BMP7, but negligibly inhibits actions of BMP2 and BMP4, to which it binds more weakly. Consonant with the original predictions from structure, sclerostin is a BMP antagonist. —GJS
Pathophysiology◆ Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell. 2003 Jun 27;113(7):905–17.
The Williams Syndrome transcription factor WSTF functions in assembly of a large chromatin-remodeling complex that mediates the recruitment of unliganded VDR to target sites in promoters. Expression of WSTF rescues the impaired recruitment of VDR to vitamin D-regulated promoters in Williams Syndrome fibroblasts. Clinically, Williams syndrome is typified by transient 1,25-dihydroxyvitamin D-mediated hypercalcemia in the first year of life. Presumably, haploinsufficiency of WSTF prevents downregulation of the 1a-hydroxylase gene by 1,25-dihydroxyvitamin D, but why only transiently, and what is different between calcium homeostasis in the first year of life and subsequent years? —GJS
◆ Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E1–9.
A stimulating review of the state of the art in hypophosphatemic disorders. The simplest model to relate PHEX to FGF23 is probably incorrect. It is suggested here that phosphate wasting induced by a phosphatonin such as FGF23 cannot fully explain osteomalacia in the phosphate wasting syndromes. There must be a separate inhibitor of bone mineralization, a “minhibin”. MEPE is a candidate molecule that could act downstream of FGF23 as a minhibin. —GJS
◆ Weber TJ, Liu S, Indridason OS, Quarles LD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res. 2003 Jul;18(7):1227–34.
The simplest explanation to relate X-linked hypophosphatemic rickets (XLH) to other phosphate-wasting disorders is that PHEX cleaves and inactivates the phosphatonin FGF23, which then accumulates in the absence of functional PHEX to cause phosphate wasting. Consistent with this view were previously reports that in treated patients with XLH, serum FGF23 levels are often (though not always) high. Here, it is shown that untreated XLH patients have normal FGF23 levels. If confirmed, these data destroy (or force modification of) a beautiful hypothesis that relates all the phosphate-wasting disorders to one another. —GJS
Physiology and metabolism◆ Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T, Manolagas SC. Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest. 2003 Jun;111(11):1651–64.
◆ Lorenzo J. A new hypothesis for how sex steroid hormones regulate bone mass. J Clin Invest. 2003 Jun;111(11):1641–3.
This paper follows on previous work by the same group to show that the estrogen analog estren, which lacks genotropic responses but has estrogen-like effects in OVX mice, signals via activation of the Src/Shc/ERK pathway or downregulation of JNK. Similar effects occur in cultured cells and in vivo, and such signals are required for the antiapoptotic actions of estren and estrogen in osteoblasts. Raloxifene does not mimic these effects. Despite these efforts, the nongenotropic effects of estrogen have not been linked directly to prevention against bone loss. —GJS
Treatment and drug effects◆ Ma YL, Bryant HU, Zeng Q, Schmidt A, Hoover J, Cole HW, Yao W, Jee WS, Sato M. New bone formation with teriparatide [human parathyroid hormone-(1-34)] is not retarded by long-term pretreatment with alendronate, estrogen, or raloxifene in ovariectomized rats. Endocrinology. 2003 May;144(5):2008–15.
The study addresses an important question, whether prior anti-resorptive therapy blunts the effects of PTH administration. The answer here is no, blunting does not occur, but bluniting of the PTH effect has been reported in other studies in animals and in human subjects.
◆ Paralkar VM, Borovecki F, Ke HZ, Cameron KO, Lefker B, Grasser WA, Owen TA, Li M, DaSilva-Jardine P, Zhou M, Dunn RL, Dumont F, Korsmeyer R, Krasney P, Brown TA, Plowchalk D, Vukicevic S, Thompson DD. An EP2 receptor-selective prostaglandin E2 agonist induces bone healing. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6736–40.
A selective agonist of the prostaglandin receptor EP2 was synthesized, shown to have anabolic effects when injected into rat bones, and then tested in two canine fracture models, where it induced dramatic healing. No systemic side effects were observed. This promises the possibility of a useful class of drugs with the anabolic bone effects of prostaglandins. —GJS
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