Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice.
Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice.
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DOI：
10.1016/j.bone.2017.08.006
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发表时间：
2017-12
期刊：
影响因子：
4.1
通讯作者：
Rosen CJ
中科院分区：
文献类型：
--
作者：
Le PT;Bishop KA;Maridas DE;Motyl KJ;Brooks DJ;Nagano K;Baron R;Bouxsein ML;Rosen CJ
迷雾小鼠(m/m)存在鸟核苷酸交换因子DOCK7基因功能突变，导致骨密度降低，骨重建解偶联，骨形成减少。在颅骨成骨细胞培养中，DOCK7被认为是成骨细胞数量和体外成骨分化的调节因子。此外，m/m组预先形成的棕色脂肪组织的神经支配和温度减少，米色脂肪细胞标志物代偿性增加。虽然低骨密度表型的部分原因是年轻小鼠的交感神经系统(SNS)驱动力较高，但对于DOCK7基因突变纯合的小鼠，衰老会产生什么影响尚不清楚。我们假设与年龄相关的骨小梁丢失和骨膜包膜扩张将在m/m发生改变。为了验证这一假设，我们在16、32、52和78周龄综合表征了m/m的骨骼表型。与年龄匹配的野生型对照组(+/+)相比，m/m组小鼠的面骨密度(ABMD)和面骨矿物质含量(Abmc)较低。同样，在m/m时，股骨和椎体的Bv/Tv、Tb.N和ConnD均降低，而Tb.Sp也增加。由于低骨密度和骨小梁减少在16周龄时就已经存在，并持续到终生，与年龄相关的骨小梁丢失没有观察到变化，突出了DOCK7在16周龄之前控制骨小梁获取或骨丢失的作用。皮质厚度在各年龄段的m/m也较低。16周时，m/m组的骨膜和骨内膜周长高于+/+组。然而，骨内膜和骨膜扩张在m/m时减弱，导致m/m在78周龄时骨膜和骨内周长低于+/+，这突显了DOCK7在对位性骨扩张中的关键作用。组织形态计量学显示，m/m几乎检测不到成骨细胞，骨髓脂肪细胞比+/+高3.5%(p=0.014)。与骨形成减少一致，成骨细胞基因ALP、Col1a1、RUNX-2、SP7和BGLAP在m/m全骨中的表达显著降低。此外，破骨细胞的标记物要么没有变化，要么被抑制。骨髓基质细胞在培养过程中迁移和运动受到抑制，衰老标志物的变化提示成骨细胞功能也受到抑制，DOCK7的表达以m/m为单位。最后，m/m耳间充质干细胞在成脂过程中油红O染色增加，突出了细胞从成骨细胞向成脂细胞的潜在转变。综上所述，DOCK7在衰老m/m中的丢失导致骨膜和皮质内包膜扩张的损害，但不改变与年龄相关的骨小梁丢失。这些研究证实DOCK7是皮质骨和松质骨量的关键调节因子，并首次证明了DOCK7在调节骨膜随年龄增长的代偿性变化中的新作用。
Misty mice (m/m) have a loss of function mutation in Dock7 gene, a guanine nucleotide exchange factor, resulting in low bone mineral density, uncoupled bone remodeling and reduced bone formation. Dock7 has been identified as a modulator of osteoblast number and in vitro osteogenic differentiation in calvarial osteoblast culture. In addition, m/m exhibit reduced preformed brown adipose tissue innervation and temperature as well as compensatory increase in beige adipocyte markers. While the low bone mineral density phenotype is in part due to higher sympathetic nervous system (SNS) drive in young mice, it is unclear what effect aging would have in mice homozygous for the mutation in the Dock7 gene. We hypothesized that age-related trabecular bone loss and periosteal envelope expansion would be altered in m/m. To test this hypothesis, we comprehensively characterized the skeletal phenotype of m/m at 16, 32, 52, and 78 wks of age. When compared to age-matched wild-type control mice (+/+), m/m had lower areal bone mineral density (aBMD) and areal bone mineral content (aBMC). Similarly, both femoral and vertebral BV/TV, Tb.N., and ConnD were decreased in m/m while there was also an increase in Tb.Sp. As low bone mineral density and decreased trabecular bone were already present at 16 wks of age in m/m and persisted throughout life, changes in age-related trabecular bone loss were not observed highlighting the role of Dock7 in controlling trabecular bone acquisition or bone loss prior to 16 wks of age. Cortical thickness was also lower in the m/m across all ages. Periosteal and endosteal circumferences were higher in m/m compared to +/+ at 16 wks. However, endosteal and periosteal expansion were attenuated in m/m, resulting in m/m having lower periosteal and endosteal circumferences by 78 wks of age compared to +/+, highlighting the critical role of Dock7 in appositional bone expansion. Histomorphometry revealed that osteoblasts were nearly undetectable in m/m and marrow adipocytes were elevated 3.5 fold over +/+ (p=0.014). Consistent with reduced bone formation, osteoblast gene expression of Alp, Col1a1, Runx-2, Sp7, and Bglap was significantly decreased in m/m whole bone. Furthermore, markers of osteoclasts were either unchanged or suppressed. Bone marrow stromal cell migration and motility were inhibited in culture and changes in senescence markers suggest that osteoblast function may also be inhibited with loss of Dock7 expression in m/m. Finally, increased Oil Red O staining in m/m ear mesenchymal stem cells during adipogenesis highlights a potential shift of cells from the osteogenic to adipogenic lineages. In summary, loss of Dock7 in the aging m/m resulted in an impairment of periosteal and endocortical envelope expansion, but did not alter age-related trabecular bone loss. These studies establish Dock7 as a critical regulator of both cortical and trabecular bone mass, and demonstrate for the first time a novel role of Dock7 in modulating compensatory changes in the periosteum with aging.
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DOI：
10.1093/rheumatology/ken177
发表时间：
2008-07
期刊：
Rheumatology (Oxford, England)
影响因子：
--
作者：
Seeman E
通讯作者：
Seeman E
DOI：
10.1016/j.ecl.2012.05.001
发表时间：
2012-09
影响因子：
4.5
作者：
Drake, Matthew T.;Khosla, Sundeep
通讯作者：
Khosla, Sundeep
影响因子：
6.2
作者：
Burge, Russel;Dawson-Hughes, Bess;Tosteson, Anna
通讯作者：
Tosteson, Anna
影响因子：
5.8
作者：
Farr, Joshua N.;Charkoudian, Nisha;Khosla, Sundeep
通讯作者：
Khosla, Sundeep
影响因子：
6
作者：
Caron, Jennifer M.;Ames, Jacquelyn J.;Brooks, Peter C.
通讯作者：
Brooks, Peter C.