Effects of age on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in humans.
Effects of age on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in humans.
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DOI：
10.1016/j.bone.2013.10.019
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发表时间：
2014-02
期刊：
影响因子：
4.1
通讯作者：
Khosla, Sundeep
中科院分区：
文献类型：
--
作者：
Roforth, Matthew M.;Fujita, Koji;McGregor, Ulrike I.;Kirmani, Salman;McCready, Louise K.;Peterson, James M.;Drake, Matthew T.;Monroe, David G.;Khosla, Sundeep
虽然衰老与人类骨形成的下降有关，但导致这种下降的分子途径仍不清楚。先前的几项临床研究表明，循环硬化素水平随着年龄的增长而增加，这增加了骨细胞产生硬化素增加导致骨形成中与年龄相关的损伤的可能性。因此，在本研究中，我们使用定量聚合酶链反应（QPCR）分析年轻（平均年龄，30.0岁）与老年（平均年龄，72.9岁）妇女针骨活检中的循环硬化蛋白水平以及硬化蛋白的骨mRNA水平。此外，我们分析了许多已知随骨骼衰老而改变的途径中的基因表达，主要基于对小鼠的研究。虽然老年女性的血清sclerostin水平比年轻女性高46%（p < 0.01），但两组之间的骨sclerostin mRNA水平没有差异（p = 0.845）。然而，与notch信号相关的基因在老年妇女的活检组织中显著上调（当作为一组进行分析时，p = 0.003）。在对118个基因的额外分析中，包括来自与骨密度和/或骨折相关的全基因组关联研究的基因、BMP/TGFβ家族基因、选定的生长因子和核受体以及Wnt/Wnt相关基因，我们发现Wnt抑制剂SFRP 1的mRNA水平显著增加（1.6倍，p = 0.0004，假发现率[q] = 0.04）。因此，我们的研究结果表明，尽管循环sclerostin水平增加，骨sclerostin mRNA水平在老年妇女中并不增加。然而，衰老与人类几个关键途径和基因的改变有关，这些途径和基因可能导致观察到的骨形成障碍。这些包括notch信号传导，其代表了增加人类骨形成的潜在治疗靶点。我们的研究进一步确定了SFRP 1的mRNA水平在人类老化骨中增加，这表明这也可能是开发年龄相关性骨丢失和骨质疏松症合成代谢疗法的可行靶点。
Although aging is associated with a decline in bone formation in humans, the molecular pathways contributing to this decline remain unclear. Several previous clinical studies have shown that circulating sclerostin levels increase with age, raising the possibility that increased production of sclerostin by osteocytes leads to the age-related impairment in bone formation. Thus, in the present study, we examined circulating sclerostin levels as well as bone mRNA levels of sclerostin using quantitative polymerase chain reaction (QPCR) analyses in needle bone biopsies from young (mean age, 30.0 years) versus old (mean age, 72.9 years) women. In addition, we analyzed the expression of genes in a number of pathways known to be altered with skeletal aging, based largely on studies in mice. While serum sclerostin levels were 46% higher (p < 0.01) in the old as compared to the young women, bone sclerostin mRNA levels were no different between the two groups (p = 0.845). However, genes related to notch signaling were significantly upregulated (p = 0.003 when analyzed as a group) in the biopsies from the old women. In an additional analysis of 118 genes including those from genome-wide association studies related to bone density and/or fracture, BMP/TGFβ family genes, selected growth factors and nuclear receptors, and Wnt/Wnt-related genes, we found that mRNA levels of the Wnt inhibitor, SFRP1, were significantly increased (by 1.6-fold, p = 0.0004, false discovery rate [q] = 0.04) in the biopsies from the old as compared to the young women. Our findings thus indicate that despite increases in circulating sclerostin levels, bone sclerostin mRNA levels do not increase in elderly women. However, aging is associated with alterations in several key pathways and genes in humans that may contribute to the observed impairment in bone formation. These include notch signaling, which represents a potential therapeutic target for increasing bone formation in humans. Our studies further identified mRNA levels of SFRP1 as being increased in aging bone in humans, suggesting that this may also represent a viable target for the development of anabolic therapies for age-related bone loss and osteoporosis.
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影响因子：
4
作者：
Ota, Kuniaki;Quint, Patrick;Ruan, Ming;Pederson, Larry;Westendorf, Jennifer J.;Khosla, Sundeep;Oursler, Merry Jo
通讯作者：
Oursler, Merry Jo
影响因子：
1.9
作者：
OBRIEN, PC
通讯作者：
OBRIEN, PC
影响因子：
6.2
作者：
Ardawi, Mohammed-Salleh M.;Al-Kadi, Hanan A.;Qari, Mohammed H.
通讯作者：
Qari, Mohammed H.
DOI：
10.1007/bf02013227
发表时间：
1978-01-01
期刊：
CALCIFIED TISSUE RESEARCH
影响因子：
--
作者：
LIPS, P;COURPRON, P;MEUNIER, PJ
通讯作者：
MEUNIER, PJ
慢性雌激素治疗对雌性小鼠年龄相关的骨质流失的影响。
影响因子：
6.2
作者：
Syed, Farhan A.;Modder, Ulrike I. L.;Roforth, Matthew;Hensen, Ira;Fraser, Daniel G.;Peterson, James M.;Oursler, Merry Jo;Khosla, Sundeep
通讯作者：
Khosla, Sundeep