Inhibition of GSK-3β rescues the impairments in bone formation and mechanical properties associated with fracture healing in osteoblast selective connexin 43 deficient mice.
Inhibition of GSK-3β rescues the impairments in bone formation and mechanical properties associated with fracture healing in osteoblast selective connexin 43 deficient mice.
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GSK-3β的抑制作用可挽救与成骨细胞选择性连接蛋白43小鼠相关的骨形成和与骨折愈合相关的机械性能的损伤。
DOI：
10.1371/journal.pone.0081399
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Donahue HJ
中科院分区：
文献类型：
--
作者：
Loiselle AE;Lloyd SA;Paul EM;Lewis GS;Donahue HJ
连接蛋白43（Cx43）是骨中最丰富的间隙连接蛋白，并且是成骨细胞分化和骨稳态所必需的。在骨折愈合过程中，Cx43在成骨细胞和骨细胞中大量表达，而Cx43缺乏会损害骨形成和愈合。在本研究中，我们选择性地从未成熟成骨细胞到骨细胞中删除成骨细胞谱系中的Cx43，并测试了以下假设：Cx43缺陷导致成骨细胞分化延迟和生物力学特性恢复受损，这是由于相对于野生型同窝仔的β-连环蛋白表达减弱。在这里，我们表明，Cx43缺乏导致愈合的矿化和重塑阶段的改变。在Cx43缺陷型骨折中，成骨基因的延迟表达标志着矿化阶段。此外，RankL/ Opg比值、破骨细胞数量和破骨细胞大小的降低表明破骨细胞骨吸收和重塑减少。这些愈合变化导致功能缺陷，如失效时极限扭矩降低所示。与愈合中的这些损伤一致，在Cx43缺陷骨折中，β-连环蛋白表达在14天和21天时减弱，而在Cx43 cKO骨折中，骨形成的负调节因子硬化蛋白（Sost）表达在21天时增加，GSK-3β（β-连环蛋白酶体降解复合物的关键组分）也是如此。此外，我们发现，Cx43缺陷性骨折愈合的改变可以通过使用氯化锂（LiCl）抑制GSK-3β活性来挽救。相对于LiCl处理的WT骨折，用LiCl处理Cx43缺陷小鼠恢复了正常的骨形成和机械性能。这项研究表明，Cx43是促进骨折愈合的潜在治疗靶点，并确定了Cx43在调节β-连环蛋白表达从而调节骨折修复期间骨形成方面以前未知的作用。
Connexin 43 (Cx43) is the most abundant gap junction protein in bone and is required for osteoblastic differentiation and bone homeostasis. During fracture healing, Cx43 is abundantly expressed in osteoblasts and osteocytes, while Cx43 deficiency impairs bone formation and healing. In the present study we selectively deleted Cx43 in the osteoblastic lineage from immature osteoblasts through osteocytes and tested the hypothesis that Cx43 deficiency results in delayed osteoblastic differentiation and impaired restoration of biomechanical properties due to attenuated β-catenin expression relative to wild type littermates. Here we show that Cx43 deficiency results in alterations in the mineralization and remodeling phases of healing. In Cx43 deficient fractures the mineralization phase is marked by delayed expression of osteogenic genes. Additionally, the decrease in the RankL/ Opg ratio, osteoclast number and osteoclast size suggest decreased osteoclast bone resorption and remodeling. These changes in healing result in functional deficits as shown by a decrease in ultimate torque at failure. Consistent with these impairments in healing, β-catenin expression is attenuated in Cx43 deficient fractures at 14 and 21 days, while Sclerostin (Sost) expression, a negative regulator of bone formation is increased in Cx43cKO fractures at 21 days, as is GSK-3β, a key component of the β-catenin proteasomal degradation complex. Furthermore, we show that alterations in healing in Cx43 deficient fractures can be rescued by inhibiting GSK-3β activity using Lithium Chloride (LiCl). Treatment of Cx43 deficient mice with LiCl restores both normal bone formation and mechanical properties relative to LiCl treated WT fractures. This study suggests that Cx43 is a potential therapeutic target to enhance fracture healing and identifies a previously unknown role for Cx43 in regulating β-catenin expression and thus bone formation during fracture repair.
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影响因子：
15.8
作者：
Chen Y;Whetstone HC;Lin AC;Nadesan P;Wei Q;Poon R;Alman BA
通讯作者：
Alman BA
影响因子：
3.3
作者：
Lecanda, F;Towler, DA;Civitelli, R
通讯作者：
Civitelli, R
影响因子：
0.7
作者：
Liu, F;Woitge, HW;Kream, BE
通讯作者：
Kream, BE
影响因子：
6.2
作者：
Bivi, Nicoletta;Condon, Keith W.;Allen, Matthew R.;Farlow, Nathan;Passeri, Giovanni;Brun, Lucas R.;Rhee, Yumie;Bellido, Teresita;Plotkin, Lilian I.
通讯作者：
Plotkin, Lilian I.
影响因子：
3.7
作者：
Gramsch, B;Gabriel, HD;Schirrmacher, K
通讯作者：
Schirrmacher, K