Global Disruption of α2A Adrenoceptor Barely Affects Bone Tissue but Minimizes the Detrimental Effects of Thyrotoxicosis on Cortical Bone (original) (raw)
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American journal of physiology. Endocrinology and metabolism, 2014
To investigate whether thyroid hormone (TH) interacts with the sympathetic nervous system (SNS) to modulate bone mass and structure, we studied the effects of daily T3 treatment in a supraphysiological dose for 12 wk on the bone of young adult mice with chronic sympathetic hyperactivity owing to double-gene disruption of adrenoceptors that negatively regulate norepinephrine release, α(2A)-AR, and α(2C)-AR (α(2A/2C)-AR(-/-) mice). As expected, T3 treatment caused a generalized decrease in the areal bone mineral density (aBMD) of WT mice (determined by DEXA), followed by deleterious effects on the trabecular and cortical bone microstructural parameters (determined by μCT) of the femur and vertebra and on the biomechanical properties (maximum load, ultimate load, and stiffness) of the femur. Surprisingly, α(2A/2C)-AR(-/-) mice were resistant to most of these T3-induced negative effects. Interestingly, the mRNA expression of osteoprotegerin, a protein that limits osteoclast activity, wa...
2011
Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via b 2 -adrenoceptor (b2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, a 2A -AR and a 2C -AR (a 2A /a 2C -ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In a 2A /a 2C -ARKO versus wild-type (WT) mice, micro-computed tomographic (mCT) analysis showed increased, better connected, and more plate-shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate-resistant acid phosphatase (TRACP) and receptor activator of NF-kB (RANK), which are osteoclast-related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine-regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial b 2 -AR mRNA expression also was similar in KO and WT littermates, whereas a 2A -, a 2B -and a 2C -AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected a 2A -, a 2B -, a 2C -and b 2 -ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5-day-old mouse fetuses and 35-day-old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective a 2 -AR agonist clonidine and to the nonspecific a-AR antagonist phentolamine. These findings suggest that b 2 -AR is not the single adrenoceptor involved in bone turnover regulation and show that a 2 -AR signaling also may mediate the SNS actions in the skeleton. ß
Role of thyroid hormones in skeletal development and bone maintenance
Endocrine reviews, 2016
The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development, adulthood and in response to injury. Future analysis of T3 action in individua...
TSH and Thyroid Hormones Both Regulate Bone Mass
Clinical Reviews in Bone and Mineral Metabolism, 2008
Thyrotoxicosis is associated with a high-turnover osteoporosis, which has been solely attributed to elevated thyroid hormone levels. Mice lacking the thyroid hormone receptors a and b establish a role for thyroid hormones in regulating bone remodeling. We show that TSH, which falls when thyroid hormones rise, directly suppresses bone remodeling, and that TSH receptor null mice have profound bone loss. We suggest that reduced TSH signaling contributes to hyperthyroid osteoporosis and that TSH and its receptor could become valuable drug targets.
The regulatory role of thyroid hormones in bone cell growth and differentiation
The Journal of nutrition, 1995
The clinical effects of thyroid hormones on bone in hypo- and hyperthyroidism are well known but their fundamental role in the regulation of bone remodeling is still poorly understood. In this review the current literature is summarized and experimental data from our laboratory are presented. The direct stimulation of bone resorption by thyroid hormones in organ culture, which in part is mediated by prostaglandins and TGF-beta, and the effect of different agents thereon are reviewed. More recent data concerning thyroid hormone action in the osteoblastic cell line MC3T3E1, are summarized. From their effect on proliferation and alkaline phosphatase activity, we conclude that thyroid hormones accelerate osteoblastic differentiation. The regulation of the transcriptional expression of certain genes by nuclear T3 receptors and their effect on osteoblastic target genes like IGF-I are reviewed. In addition a novel role of triiodothyronine as inhibitor of growth factor induced transcription...
The expression of thyroid hormone receptors in human bone
Bone, 1997
The mechanism of action of thyroid hormones on bone is poorly understood. Thyroid hormones may act on bone cells either indirectly by increasing secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), or directly by influencing target genes via specific nuclear receptors. The presence of thyroid hormone receptors (TRs) has been demonstrated in human and rodent osteoblast-like cells and cell lines and recently in osteoclasts derived from an osteoclastoma in vitro. However, their presence in human bone in situ has not been reported. We have used specific polyclonal antibodies to TR-al, -or2, and -131 to investigate the expression of these receptors in sections of human osteophytes and heterotopic bone. Osteoblasts and osteoclasts were identified by alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), respectively, whereas chondrocytes were identified morphologically. At sites of endochondral and intramembranous bone formation, TR-I~I and the splice variant -a2 were widely expressed by proliferating, mature, and hypertrophic chondrocytes and also in cells within the fibrous tissue and at the bone forming surfaces, respectively. They were also detected in osteoblasts, osteoclasts, and a few osteocytes at sites of bone remodeling. In contrast, TR-cd was the least expressed and was present mainly in osteoblasts at remodeling sites and in a few mature and undifferentiated chondrocytes. Our results show, for the first time, the presence and distribution of TRs in human bone in situ and suggest that the skeletal actions of thyroid hormones may be mediated via these receptors. Further studies are required to define the role of the individual receptor isoforms in bone metabolism. (Bone 21:137-142; 1997) © 1997 by Elsevier Science Inc. All rights reserved.
Thyroid-stimulating hormone, thyroid hormones, and bone loss
Current Osteoporosis Reports, 2009
It has become accepted by virtue of rich anecdotal experience and clinical research that thyrotoxicosis is associated with high-turnover osteoporosis. The bone loss, primarily due to accelerated resorption that is not compensated by a coupled increase in bone formation, has been attributed solely to elevated thyroid hormone levels. Evidence using mice lacking the thyroid hormone receptors α and β establishes a role for thyroid hormones in regulating bone remodeling but does not exclude an independent action of thyroid-stimulating hormone (TSH), levels of which are low in hyperthyroid states, even when thyroid hormones are normal, as after thyroxine supplementation and in subclinical hyperthyroidism. We show that TSH directly suppresses bone remodeling and that TSH receptor null mice have profound bone loss, suggesting that reduced TSH signaling contributes to hyperthyroid osteoporosis. TSH and its receptor could become valuable drug targets in treating bone loss.