BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers: August 2003 selections
DOI:10.1138/2003099
Bone modeling and remodeling◆ Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, Karsenty G, Taniguchi T, Takayanagi H. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev. 2003 Aug 15;17(16):1979–91.
Stat1 deficiency leads to increased osteoclastogenesis, as expected from its role as a signaling molecule in the interferon pathway. But Stat1(-/-) mice have markedly increased bone volumes and bone formation rates. This phenotype can be explained by an effect of Stat1 to sequester Runx2 (Cbfa1) in the cytoplasm and thereby inhibit osteoblast gene expression, an unexpected form of crosstalk between two signaling pathways. —GJS
Pathophysiology◆ Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest. 2003 Sep;112(5):785–94.
The search for phosphatonins has identified FGF23 as a prime candidate. Not only is FGF23 produced by tumors associated with phosphate wasting, but mutations in FGF23 cause autosomal dominant hypophosphatemic rickets. Another gene expressed in tumor-induced osteomalacia is secreted frizzled-related protein 4 (SFRP4), an inhibitor of thewnt pathway, and this paper reports that SFRP4 is a potent phosphaturic agent. Serum levels of SFRP4 were not increased in a single patient with tumor-induced osteomalacia, however. There is room for more than one phosphatonin, and SFRP4 is a very good candidate. —GJS
◆ Danova NA, Colopy SA, Radtke CL, Kalscheur VL, Markel MD, Vanderby R, McCabe RP, Escarcega AJ, Muir P. Degradation of bone structural properties by accumulation and coalescence of microcracks. Bone. 2003 Aug;33(2):197–205.
Microcrack origination and progression probably precedes the occurrence of structural failure. The structural factors responsible for the origination, progression, and cessation of microdamage remain poorly defined. This analysis suggests that changes in bone external structure can compensate for loss of material stiffness.
◆ Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003 Sep;112(5):683–92.
About one-half of patients with fibrous dysplasia or McCune-Albright syndrome have phosphate wasting, which could theoretically be explained either by the secretion of a phosphatonin from the lesions or by expression of constitutively active Gs in the kidney. Here it is reported that osteoblasts from normal bone and fibrous cells from dysplastic bone express the phosphatonin FGF23. Serum levels of FGF23 are high in hypophosphatemic patients, but not in normophosphatemic patients with fibrous dysplasia. It is suggested that the burden of fibrous tissue rather than increased production by fibrous cells is the determinant of FGF23 levels and hypophosphatemia in fibrous dysplasia. —GJS
Physiology and metabolism◆ Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K. Proton-sensing G-protein-coupled receptors. Nature. 2003 Sep 4;425(6953):93–8.
A fortuitous observation led these workers to identify a G protein-coupled receptor, OGR4, as a sensor of pH in the physiological range. OGR4 is strongly expressed in osteoblasts and osteocytes, and osteoblasts were shown to release inositol phosphate in response to mild acidosis. The system thus defined could play a central role in the resorption of bone in response to systemic acidosis. —GJS
◆ Oreffo RO, Lashbrooke B, Roach HI, Clarke NM, Cooper C. Maternal protein deficiency affects mesenchymal stem cell activity in the developing offspring. Bone. 2003 Jul;33(1):100–7.
I'm not sure about the veracity of the purported fetal origins of disease or what can be done about them, but this article is a valiant attempt at hypothesis testing. The results seem to argue against, not for, programming in the first year of life. The cellular abnormalities in the offspring associated with maternal protein depletion were transient and returned to (or were higher than) the “tracking” level determined in utero.
Treatment and drug effects◆ Boivin G, Lips P, Ott SM, Harper KD, Sarkar S, Pinette KV, Meunier PJ. Contribution of raloxifene and calcium and vitamin D3 supplementation to the increase of the degree of mineralization of bone in postmenopausal women. J Clin Endocrinol Metab. 2003 Sep;88(9):4199–205.
The increase in bone mineral density with antiresorptive drugs is the result of the filling of the three components of the remodeling transient (the empty resorption cavities, the unmineralized new bone formed and older but still incompletely secondarily mineralized bone). The extent of the increase with raloxifene was not very different from that produced by calcium supplementation, yet fracture rates differed.
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