BoneKEy-Osteovision | Not To Be Missed
Clinical and basic research papers: October 2003 selections
DOI:10.1138/20040123
Bone modeling and remodeling◆ Abe E, Marians RC, Yu W, Wu XB, Ando T, Li Y, Iqbal J, Eldeiry L, Rajendren G, Blair HC, Davies TF, Zaidi M. TSH is a negative regulator of skeletal remodeling. Cell. 2003 Oct 17;115(2):151–62.
Mice in which the thyrotropin (TSH) gene is deleted have osteoporosis. Curiously, even heterozygotes are affected, although they have normal thyroid function — 50% of the normal complement of TSH receptors is sufficient for thyroid cells, but not for bone cells. The effects of thyroid disease on bone have previously been viewed as direct effects of thyroid hormone, but this paper goes on to report that TSH receptors are present on osteoblasts and osteoclasts and that via these receptors, TSH inhibits osteoclast formation and osteoblast differentiation. —GJS
◆ Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003 Oct 23;425(6960):841–6.
◆ Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003 Oct 23;425(6960):836–41.
Bone is the preferred site for hematopoiesis, but how? Mice with activating mutation of the parathyroid hormone (PTH) receptor have an expanded stem cell niche, as do mice that are treated with PTH. —GJS
Genetics◆ Bastepe M, Frohlich LF, Hendy GN, Indridason OS, Josse RG, Koshiyama H, Korkko J, Nakamoto JM, Rosenbloom AL, Slyper AH, Sugimoto T, Tsatsoulis A, Crawford JD, Juppner H. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest. 2003 Oct;112(8):1255–63.
Both forms of pseudohypoparathyroidism are imprinted: renal insensitivity to parathyroid hormone (PTH) can only be inherited from the mother. The locus of the disorder is the gene that encodes Gsα the coupling protein for the PTH receptor, and in isolated PTH insensitivity, pseudohypoparathyroidism type 1b, the problem is traceable to abnormal gene methylation, but there is no mutation within the gene to account for the problem. Now the mutation has been identified, 280 kb upstream of the Gsα gene, within the gene encoding syntaxin-16, a SNARE protein. This identifies a far upstream locus control region for parental imprinting. —GJS
◆ Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C, Arnold A. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med. 2003 Oct 30;349(18):1722–9.
Inherited mutations in the HRPT2 gene are the cause of hereditary hyperparathyroidism-jaw tumor syndrome, in which parathyroid carcinoma is considerably more common than in sporadic primary hyperparathyroidism. Here, it is reported that 10 of 15 parathyroid carcinomas had somatic HRPT2 mutations, and there were also germline mutations in three of them. The HRPT2 gene is the most important oncogene yet found in parathyroid carcinoma. Patients with sporadic parathyroid carcinoma should probably be screened for HRPT2 mutations for purposes of genetic counseling. —GJS
Pathophysiology◆ Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: a “forme fruste” of an old disease. J Clin Endocrinol Metab. 2003 Nov;88(11):5348–52.
Normocalcemic patients are reported who have high parathyroid hormone (PTH) levels and approximately the same ratio of PTH to calcium as do patients with typical primary hyperparathyroidism. It is proposed that normocalcemic patients with high PTH levels represent the incipient stage of primary hyperparathyroidism, and some indeed progressed to hypercalcemia over a short follow-up period. It may well be that this patient group is heterogeneous; however, the phenotype is also consistent with mild forms of PTH resistance. —GJS
Physiology and metabolism◆ Moverare S, Venken K, Eriksson AL, Andersson N, Skrtic S, Wergedal J, Mohan S, Salmon P, Bouillon R, Gustafsson JA, Vanderschueren D, Ohlsson C. Differential effects on bone of estrogen receptor alpha and androgen receptor activation in orchidectomized adult male mice. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13573–8.
In orchidectomized male mice, the nonaromatizable androgen 5α-dihydrotestosterone protects against bone loss in wild-type (WT) and estrogen receptor (ER)-inactivated mice; 17 β-estradiol also protects WT mice. Its effects are mediated by ER-α not ER-β and could not be mediated by the androgen receptor. Together with a previous paper (Sims NA et al J. Clin. Invest. 2003 May 1; 111(9):1319–1327), the results show that the promiscuity of steroid hormone receptors that has been observed in vitro does not hold in gonadectomy models. MicroCT studies show that effects of estrogen and androgen are clearly distinct. —GJS
Several points seem to be becoming clear in male rodents. Estrogen receptor (ER)-β is irrelevant. Estrogen works through ER-α to preserve trabecular thickness and number, in part through growth hormone/insulin-like growth factor-1. Androgen activation, through its androgen receptor, preserves the number of trabeculae, not thickness.
◆ VanHouten JN, Dann P, Stewart AF, Watson CJ, Pollak M, Karaplis AC, Wysolmerski JJ. Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation. J Clin Invest. 2003 Nov;112(9):1429–36.
Mammals can sacrifice skeletal mineral to provide calcium to their offspring during lactation, even in the absence of parathyroid hormone (PTH) or vitamin D. Parathyroid hormone-related protein (PTHrP) is secreted into milk and possibly into blood during lactation and is a candidate mediator of bone loss. This paper shows that ablation of the PTHrP gene in mouse mammary glands prevents bone turnover, reduces bone loss, and also prevents compensatory increases in 1,25-dihydroxyvitamin D. PTHrP, otherwise a tissue cytokine, is a circulating hormone during lactation and regulates the compensation of kidney and bone to calcium loss. PTHrP is also absent from milk in this model, and it will be important to examine the development of neonates carefully for effects of its absence. —GJS
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