BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers: May 2003 selections
DOI:10.1138/2003096
Bone modeling and remodeling◆ Akkus O, Polyakova-Akkus A, Adar F, Schaffler MB. Aging of microstructural compartments in human compact bone. J Bone Miner Res. 2003 Jun;18(6):1012–9.
What is new here is the notion that secondary mineralization can continue for 20 years in unremodeled bone while secondary osteons limit this process so that inhibiting remodeling may contribute to brittle bones. Whether it does or not remains to be proven.
◆ Fitzpatrick LA, Buzas E, Gagne TJ, Nagy A, Horvath C, Ferencz V, Mester A, Kari B, Ruan M, Falus A, Barsony J. Targeted deletion of histidine decarboxylase gene in mice increases bone formation and protects against ovariectomy-induced bone loss. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6027–32.
Systemic mastocytosis can be associated with osteolysis or osteosclerosis. The bone phenotype of mice with targeted deletion of the histidine decarboxylase gene is reported here. There is both increased bone formation and a marked decrease in osteoclast number, with protection against bone loss induced by OVX. Serum levels of calcitriol are increased in histidine decarboxylase(-/-) mice with a reciprocal decrease in PTH levels but it is not clear how these changes are related to the bone phenotype. —GJS
◆ Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G, Harris SE, Gallwitz W, Kim KB, Hu S, Crews CM, Mundy GR. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest. 2003 Jun;111(11):1771–82.
The ubiquitin-proteasome pathway degrades many short-lived proteins and inhibitors of the proteasome pathway increases bone formation, in part, by increasing BMP-2 gene expression, and do osteoblast differentiation in vitro and bone formation in vivo. The proteasome inhibitors increase BMP-2 promoter activity and BMP-2 mRNA. BMP-2 stimulates osteoblast differentiation in an autocrine fashion. This pathway offers many molecular targets for bone formation stimulating drugs. —ES
◆ Karsenty G. The complexities of skeletal biology. Nature. 2003 May 15;423(6937):316–8.
◆ Mariani FV, Martin GR. Deciphering skeletal patterning: clues from the limb. Nature. 2003 May 15;423(6937):319–25.
◆ Helms JA, Schneider RA. Cranial skeletal biology. Nature. 2003 May 15;423(6937):326–31.
◆ Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003 May 15;423(6937):332–6.
◆ Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003 May 15;423(6937):337–42.
◆ Zelzer E, Olsen BR. The genetic basis for skeletal diseases. Nature. 2003 May 15;423(6937):343–8.
◆ Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature. 2003 May 15;423(6937):349–55.
Negotiating this series of seven articles is no cruise on the Nile but it is a humbling learning experience not to be missed. The authors take us on a journey through skeletal development from mesenchymal cell condensations, to skeletal patterning of limbs and cranial structures, long bone development negotiating the regulatory pathways of the growth plate, synthesis, differentiation and interactions of bone resorbing and forming cells, mutations in nature that reveal regulatory pathways undreamt of by the candidate gene approach. Slowly, and don't miss out on the bibliography provided at the end of each article.
◆ Yu K, Xu J, Liu Z, Sosic D, Shao J, Olson EN, Towler DA, Ornitz DM. Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development. 2003 Jul 1;130(13):3063–3074.
In a novel approach to the inactivation of skeletal genes, the FGF receptor 2 gene was targeted in cartilage and bone cells derived from mesenchymal condensations by the use of cre recombinase driven by the early mesenchymal transcription factor Dermo1. Conditionally targeted mice are dwarfed, with markedly reduced hypertrophic zones in their growth plates. Cortices are thin and trabecular bone is reduced, due to a decrease in osteoblast proliferation and markedly reduced osteoblast function and mineral apposition rate. FGFs are required not only for osteoblast development but also for their normal synthetic function. —GJS
Genetics◆ Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PV, Robinson JA, Bhat B, Marzolf J, Moran RA, Bex F. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res. 2003 Jun;18(6):960–74.
So much for the candidate gene approach. The LRP5 gene would never have been one. A mutation (G171V) in this gene produces thicker cortices, more and thicker trabeculae and increased bone strength in the axial and appendicular skeleton in transgenic mice similar to the phenotype found in human subjects. Is this the door to the mechanostat? We'll see. —ES
Pathophysiology◆ Bonyadi M, Waldman SD, Liu D, Aubin JE, Grynpas MD, Stanford WL. Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1/Ly-6A null mice. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5840–5.
Knockout of the gene for Sca-1/Ly-6A, a GPI-linked cell surface protein that is expressed on hematopoetic cells, lymphocytes and osteoblasts, produces age-dependent osteoporosis with reduced numbers of both osteoclasts (a defect that is attributable to an osteoblast signaling defect) and of osteoblast precursors. It is suggested that mesenchymal progenitor self-renewal is defective, as is hematopoietic stem cell renewal in Sca-1 -/- mice, but we do not yet have sufficiently refined methods to be sure. —GJS
◆ Chen H, Hewison M, Hu B, Adams JS. Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6109–14.
New World monkeys are resistant to vitamin D. A similar mechanism of vitamin D resistance is reported here in a patient with vitamin D resistant rickets and a normal vitamin D receptor. Mixing experiments showed an inhibitor of receptor binding to DNA in the patient's cells, and this was tentatively identified as a heterogenous nuclear ribonuclear protein, suggesting a similar mechanism of inhibition to that in New World monkeys. —GJS
Physiology and metabolism◆ Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003 Jun;9(6):653–60.
◆ Cleaver O, Melton DA. Endothelial signaling during development. Nat Med. 2003 Jun;9(6):661–8.
◆ Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003 Jun;9(6):669–76.
◆ Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003 Jun;9(6):677–84.
◆ Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003 Jun;9(6):685–93.
◆ Yla-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med. 2003 Jun;9(6):694–701.
◆ Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003 Jun;9(6):702–12.
◆ McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med. 2003 Jun;9(6):713–25.
A blood supply is useful in skeletal health yet it is an embarrassingly neglected area in bone metabolism. In the above series of eight articles, discussions of angiogenesis in health and disease, endothelial signaling during development, the biology of vascular endothelial growth factor, regulation of angiogenesis by hypoxia, molecular egulation of vessel maturation and therapeutic use of stem and progenitor cell transplantation, and imaging of angiogenesis are discussed. Although the topics are general and not directly addressed to skeletal growth, there are important clues for lateral thinkers. —ES
◆ Ha H, Kwak HB, Lee SK, Na DS, Rudd CE, Lee ZH, Kim HH. Membrane rafts play a crucial role in receptor activator of nuclear factor kappaB signaling and osteoclast function. J Biol Chem. 2003 May 16;278(20):18573–80.
The receptors for several TNF family members assemble signaling complexes on membrane rafts. This paper reports that RANK and TRAF6 are assembled on rafts in the plasma membrane of osteoclasts. Disruption of rafts inhibits AKT signaling but not NFkB or MAPK signaling, and partially inhibits bone resorption by osteoclasts. The assembly of a signaling complex on membrane rafts may be important for some, but not all pathways downstream of RANK in osteoclasts. —GJS
◆ Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003 May 22;423(6938):409–14.
Recommended. —ES
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