BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers: April 2003 selections
DOI:10.1138/2003091
Bone modeling and remodeling◆ Ciarelli TE, Fyhrie DP, Parfitt AM. Effects of vertebral bone fragility and bone formation rate on the mineralization levels of cancellous bone from white females. Bone. 2003 Mar;32(3):311–5.
Goldilock wanted the Three Bear's porridge to be just right - not too hot and not too cold. Tissue mineral density is Gaussian in distribution in normal subjects but bimodal in patients with fractures: low mineralization causing reduced stiffness and high mineralization resulting in reduced toughness.
◆ Jordan GR, Loveridge N, Power J, Clarke MT, Parker M, Reeve J. The ratio of osteocytic incorporation to bone matrix formation in femoral neck cancellous bone: an enhanced osteoblast work rate in the vicinity of hip osteoarthritis. Calcif Tissue Int. 2003 Mar;72(3):190–6.
Osteocytes, the most abundant and most neglected cells in bone are getting a little attention. Some interesting ideas and thinking in this paper.
◆ Kawaida R, Ohtsuka T, Okutsu J, Takahashi T, Kadono Y, Oda H, Hikita A, Nakamura K, Tanaka S, Furukawa H. Jun Dimerization Protein 2 (JDP2), a Member of the AP-1 Family of Transcription Factor, Mediates Osteoclast Differentiation Induced by RANKL. J Exp Med. 2003 Apr 21;197(8):1029–35.
Several recent studies have implicated AP-1 as essential to RANKL regulation of osteoclasts. Here, another member of the AP-1 family, Jun dimerization protein 2 (JDP2) is identified as being upregulated by RANKL in RAW 264.7 cells and mouse bone marrow macrophages. Transfection of JDP2 activates the TRAP and cathepsin K gene promoters and enhances responses to RANKL. Antisense oligonucleotides to JDP2 markedly reduce osteoclast differentiation of RAW cells in response to RANKL. —GJS
◆ Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS. Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab. 2003 Jan;88(1):204–10.
The role of estrogen and testosterone on bone loss in men is not well understood. Read this with Falahati-Nini et al. and Taxel et al. However, what do changes in bone resorption and formation markers in short term studies reflect in morphological terms?
◆ Roschger P, Gupta HS, Berzlanovich A, Ittner G, Dempster DW, Fratzl P, Cosman F, Parisien M, Lindsay R, Nieves JW, Klaushofer K. Constant mineralization density distribution in cancellous human bone. Bone. 2003 Mar;32(3):316–23.
Mineral density of tissue does not differ by ethnicity, skeletal site, age or sex but does in osteomalacia or following alendronate.
Genetics◆ Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med. 2003 Apr;9(4):399–406.
The grey-lethal mutation in the mouse has been identified by positional cloning and BAC rescue of the phenotype. The mutation affects a cytoplasmic protein of unknown function that is present in osteoclasts, melanocytes and other tissues; the cellular phenotype of defective cytoskeletal rearrangements in osteoclasts and melanocytes is consistent with a role of the protein in cell polarization or vesicle trafficking. One of 19 patients with autosomal recessive osteopetrosis also had a mutation in the grey-lethal gene. Like the grey-lethal gene, the Mitf gene is required for osteoclast and melanocyte function, but the relationship between the two cells remains inscrutable. —GJS
Pathophysiology◆ Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. 2003 Apr;111(8):1221–30.
A ground-breaking technique was used to isolate RANKL+ stromal cells from human bone marrow by flow cytometry. The cell surface density of RANKL is increased on marrow stromal cells that are isolated from postmenopausal women and also on their B-lymphocytes and T-lymphocytes; the cell surface level of RANKL on all three cell types is reduced to that of premenopausal women by estrogen treatment. RANKL levels on marrow stromal cells, B-cells and T-cells are correlated with markers of bone turnover. Are these changes direct consequences of estrogen deficiency or indirect consequences induced by cytokines? —GJS
◆ Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003 Apr 24;348(17):1656–63.
A new assay for serum FGF23 in phosphate-wasting disorders is reported. The serum level of FGF23 is detectable in most normal subjects. Most patients with oncogenic osteomalacia have elevated levels that are normalized by resection of the tumor. FGF23 levels are also high in some patients with X-linked hypophosphatemia, but a substantial proportion of patients with X-linked hypophosphatemia have normal FGF-23 levels. Is the syndrome heterogeneous or do factors such as treatment with oral phosphate and vitamin D obscure the true role of FGF23? —GJS
Physiology and metabolism◆ Khundmiri SJ, Rane MJ, Lederer ED. Parathyroid hormone regulation of type II sodium-phosphate cotransporters is dependent on an A kinase anchoring protein. J Biol Chem. 2003 Mar 21;278(12):10134–41.
An anchoring protein for PKA (AKAP) associates with the sodium-phosphate cotransporter in OK cells (NaPi4), cAMP phosphorylates the transporter in immunoprecipitated complexes, an AKAP blocking peptide prevents the inhibition of phosphate transport by PTH in OK cells, and a mutant form of AKAP does not support phosphate transport in a reconstituted system in HEK293 cells. AKAP may be important in the formation of an oligomeric signaling complex including PKA and the sodium phosphate cotransporter. —GJS
◆ Tu Q, Pi M, Karsenty G, Simpson L, Liu S, Quarles LD. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest. 2003 Apr;111(7):1029–37.
◆ Kos CH, Karaplis AC, Peng JB, Hediger MA, Goltzman D, Mohammad KS, Guise TA, Pollak MR. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest. 2003 Apr;111(7):1021–8.
Mice in whom the calcium-sensing receptor are ablated are a model of neonatal severe hyperparathyroidism, and have gross abnormalies of cartilaginous growth plates and of bone. By transferring this trait onto a genetically hypoparathyroid background (created either by deletion of the PTH gene or deletion of the parathyroid glands), these two papers show that rachitic and bony changes in the syndrome are not present when hyperparathyroidism is prevented. Though the notion is appealing that direct calcium sensing would regulate the function of cartilage or bone, there is thus no evidence here for an essential and nonredundant function of the calcium-sensing receptor in either tissue. —GJS
Treatment and drug effects◆ Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek IA, Valanis BG. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003 May 8;348(19):1839–54.
Does HRT have any role to play in postmenopausal health? Read this and don't be tricked. Read Deborah Grady's editorial that accompanies the paper.
◆ Komatsubara S, Mori S, Mashiba T, Ito M, Li J, Kaji Y, Akiyama T, Miyamoto K, Cao Y, Kawanishi J, Norimatsu H. Long-term treatment of incadronate disodium accumulates microdamage but improves the trabecular bone microarchitecture in dog vertebra. J Bone Miner Res. 2003 Mar;18(3):512–20.
This is a wonderful paper. It should be read with the work of Mashiba and others. Incadronate suppressed trabecular remodeling and increased microdamage accumulation. In all these studies the antiresorptive is given to normal animals. Remodeling suppression from a normal tissue mineral density may result in microdamage. Will this occur when remodeling is suppressed in a bone with a low tissue mineral density which increases into the normal range?
◆ Misof BM, Roschger P, Cosman F, Kurland ES, Tesch W, Messmer P, Dempster DW, Nieves J, Shane E, Fratzl P, Klaushofer K, Bilezikian J, Lindsay R. Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment. J Clin Endocrinol Metab. 2003 Mar;88(3):1150–6.
Is bone mineral density more apparent than real? We have many problems in the nomenclature in this field. The distinction between bone tissue mass and the degree of its mineralization must be appreciated if the effects of drug therapy on structure and material properties of bone are to be understood.
◆ Paschalis EP, Burr DB, Mendelsohn R, Hock JM, Boskey AL. Bone mineral and collagen quality in humeri of ovariectomized cynomolgus monkeys given rhPTH(1-34) for 18 months. J Bone Miner Res. 2003 Apr;18(4):769–75.
Little attention has been given to the effects of aging and drug therapy on bone collagen. rhPTH(1-34) reversibly influence cortical bone mineral-to-matrix ratio, mineral crystal maturity, and collagen cross-link ratio.
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