BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers: February and March 2003 selections
DOI:10.1138/2003089
Bone modeling and remodeling◆ Faccio R, Takeshita S, Zallone A, Ross FP, Teitelbaum SL. c-Fms and the avb3 integrin collaborate during osteoclast differentiation. J Clin Invest. 2003 Mar;111(5):749–58.
Osteoclast precursors from avb3(-/-) mice do not form osteoclasts normally in vitro. This phenotype is rescued by high concentrations of M-CSF, suggesting that matrix adhesion cooperates with extracellular signaling to bring about osteoclast formation. It is shown here that M-CSF and avb3 both signal for osteoclastogenesis through ERK and c-Fos and that rescue of osteoclastogenesis by M-CSF is c-Fos-dependent. Expression of c-Fos does not permit bone resorption by avb3(-/-) osteoclasts, however. Together with the recent paper by Takayanagi et al., showing that activation of the master gene NFAT is c-Fos dependent, the present results confirm that c-Fos has a central role that links multiple signaling pathways in osteoclast formation. —GJS
◆ Maeda Y, Noda M. Coordinated development of embryonic long bone on chorioallantoic membrane in ovo prevents perichondrium-derived suppressive signals against cartilage growth. Bone 2003 Jan;32(1):27–34.
Recommended. —ES
◆ Sugatani T, Alvarez U, Hruska KA. PTEN regulates RANKL- and osteopontin-stimulated signal transduction during osteoclast differentiation and cell motility. J Biol Chem. 2003 Feb 14;278(7):5001–8.
PTEN is a lipid phosphatase that degrades and thereby inhibits signaling by AKT. Here, it is shown that PTEN works downstream of AKT to block pathways by which RANKL induces survival and differentiation of osteoclast precursors, including crosstalk with the NFkB pathway, and also inhibits pathways by which osteopontin induces migration of osteoclast precursors. — GJS
Diagnosis◆ Khoury MJ, McCabe LL, McCabe ER. Population screening in the age of genomic medicine. N Engl J Med 2003 Jan 2;348(1):50–8.
Recommended. —ES
Epidemiology◆ Hui SL, Dimeglio LA, Longcope C, Peacock M, McClintock R, Perkins AJ, Johnston CC Jr. Difference in bone mass between black and white American children: attributable to body build, sex hormone levels, or bone turnover? J Clin Endocrinol Metab 2003 Feb;88(2):642–9.
Recommended. —ES
◆ Tinetti ME. Clinical practice. Preventing falls in elderly persons. N Engl J Med 2003 Jan 2;348(1):42–9.
Recommended. — ES
◆ Van Pottelbergh I, Goemaere S, Zmierczak H, De Bacquer D, Kaufman JM. Deficient acquisition of bone during maturation underlies idiopathic osteoporosis in men: evidence from a three-generation family study. J Bone Miner Res 2003 Feb;18 (2):303–11.
The authors report deficits in bone size and volumetric density but not increased bone remodelling in the relatives of men with fractures observations consistent with the notion that the structural and biochemical basis of bone fragility in old age has its origins in growth and this role may be relatively more important in men than in women. —ES
Pathophysiology◆ Hewison M, Kantorovich V, Liker HR, Van Herle AJ, Cohan P, Zehnder D, Adams JS. Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. J Bone Miner Res. 2003 Mar;18(3):579–82.
Macrophages produce 1,25-dihydroxyvitamin D in granulomas. This case report finds 1a-hydroxylase in tumor-associated macrophages and suggests that in lymphoma, it is such macrophages, not the malignant cells themselves, that cause hypercalcemia by secreting 1,25-dihydroxyvitamin D. — GJS
◆ Qian J, Colbert MC, Witte D, Kuan CY, Gruenstein E, Osinska H, Lanske B, Kronenberg HM, Clemens TL. Midgestational lethality in mice lacking the parathyroid hormone (PTH)/PTH-related peptide receptor is associated with abrupt cardiomyocyte death. Endocrinology. 2003 Mar;144(3):1053–61.
PTHrP(-/-) mice survive to birth despite a severe chondrodysplasia, but PTH1R(-/-) mice mostly die in midgestation. Death is associated with massive cardiomyocyte death (by a mechanism other than apoptosis). PTH1R(-/-) cardiomyocytes have markedly abnormal mitochondria, a lesion that is suggested to be associated with abnormal intracellular calcium. This begs the question of what ligand would be involved in survival of normal cardiomyocytes or death of PTH1R(-/-) cardiomyocytes. One possibility is that PTHrP, whose blood levels are very high in receptor knockout mice, kills cardiomyocytes by binding to another receptor. —GJS
◆ Ritchlin CT, Haas-Smith SA, Li P, Hicks DG, Schwarz EM. Mechanisms of TNF-a- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest. 2003 Mar;111(6):821–31.
Why is joint destruction so prominent in psoriatic arthritis? Ritchlin et al. report a marked increase in circulating osteoblast precursors in patients with psoriatic arthritis, compared with other forms of arthritis. Circulating mononuclear cells from psoriatic arthritis patients secrete TNF-a and form osteoclasts without addition of M-CSF or RANKL. These circulating precursors may migrate to inflammatory sites to erode subchondral bone. —GJS
Physiology and metabolism◆ Komarova SV, Pilkington MF, Weidema AF, Dixon SJ, Sims SM. RANK ligand-induced elevation of cytosolic Ca2+ accelerates nuclear translocation of nuclear factor kappa B in osteoclasts. J Biol Chem. 2003 Mar 7;278(10):8286–93.
This confirms other recent reports that calcium signaling is essential to osteoclast activation. Here, it is reported that chelation of intracellular calcium prevents RANKL from inducing nuclear translocation of NFkB and from promoting the survival of osteoclasts. Phospholipase C is proposed as the mediator of RANKL's effect. —GJS
◆ Krishnan V, Moore TL, Ma YL, Helvering LM, Frolik CA, Valasek KM, Ducy P, Geiser AG. Parathyroid hormone bone anabolic action requires cbfa1/runx2-dependent signaling. Mol Endocrinol. 2003 Mar;17(3):423–35.
PTH induces both cbfa1 protein and the transcriptional activity of cbfa1. The “anabolic” effect of PTH in a metatarsal organ culture assay is blocked by antisense oligonucleotides to cbfa1. Effects of PTH on activation of cbfa1 are concentration and time-dependent, suggesting a complex interplay as one determinant of the anabolic effect of PTH. —GJS
◆ Wang Q, Xie Y, Du QS, Wu XJ, Feng X, Mei L, McDonald JM, Xiong WC. Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin. J Cell Biol. 2003 Feb 17;160(4):565–75.
The tyrosine kinase Pyk-2 is involved in osteoclast signaling and gelsolin, a protein that regulates actin assembly, has previously been shown to be important in osteoclast podocyte function. Here, it is shown that Pyk-2 associates directly with gelsolin, phosphorylates it, and decreases gelsolin binding to actin monomer. Pyk-2 function is required for assembly of the actin ring, probably requiring the Pyk-2/gelsolin interaction. —GJS
Treatment and drug effects◆ Bischoff HA, Stahelin HB, Dick W, Akos R, Knecht M, Salis C, Nebiker M, Theiler R, Pfeifer M, Begerow B, Lew RA, Conzelmann M. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 2003; 2003 Feb;18(2):343–51.
Recommended. —ES
◆ Frith JC, Rogers MJ. Antagonistic effects of different classes of bisphosphonates in osteoclasts and macrophages in vitro. J Bone Miner Res 2003 Feb;18(2):204–12.
Nitrogen-containing bisphosphonates preventing protein prenylation in osteoclasts. Non-nitrogen-containing bisphosphonates resulting in osteoclast apoptosis. Combined therapy may enhance the antiresorptive effect of a low concentration, but may antagonize effects of higher concentrations, of nitrogen-containing bisphosphonates. —ES
◆ Hauselmann HJ, Rizzoli R. A comprehensive review of treatments for postmenopausal osteoporosis. Osteoporos Int 2003 Jan;14(1):2–12.
Recommended. —ES
◆ Marcus R, Wang O, Satterwhite J, Mitlak B. The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. J Bone Miner Res 2003 Jan;18(1):18–23.
Intermittent PTH decreased vertebral fracture risk in patients irrespective of age or baseline BMD or number of prevalent basis fractures. —ES
◆ Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003 Jan 23;348(4):287–94.
This prospective cohort study of 2,322 men revealed a correlation between fracture risk and serum retinol levels. This fits with a considerable body of previous epidemiological evidence, some of which was reviewed by Tucker KL. Should the recommended daily allowance of vitamin A be reduced? —GJS
◆ Rehman Q, Lang TF, Arnaud CD, Modin GW, Lane NE. Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporos Int 2003 Jan;14(1):77–81.
Intermittent PTH appears to increase vertebral body cross sectional area, an effect maintained after stopping treatment. Estimated vertebral compressive strength increased by over 200%. —ES
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