Osteocytic Connexin43 Channels Regulate Bone-Muscle Crosstalk.
Osteocytic Connexin43 Channels Regulate Bone-Muscle Crosstalk.
复制标题
骨细胞连接蛋白 43 通道调节骨-肌肉串扰
作者：
Li G;Zhang L;Ning K;Yang B;Acosta FM;Shang P;Jiang JX;Xu H
骨骼-肌肉串扰在骨骼生物力学功能、多种病理状态的进展以及局部和远程细胞环境的调节中起着重要的作用。以前的工作表明，成骨细胞中连接蛋白(Cx)43的缺失，从而导致骨细胞间接损害骨骼肌的形成和功能。然而，Cx43形成的缝隙连接通道(GJS)和半通道(HCS)在骨-肌肉串扰中各自的作用还知之甚少。为此，我们使用了两种表达显性负性突变体的Cx43骨细胞特异性转基因小鼠模型Δ130-136(Gjs和Hcs功能被抑制)和R76W(仅Gjs功能被阻断)，以确定这两种类型的Cx43通道对邻近骨骼肌的影响。阻断Δ130136小鼠骨细胞Cx43GJS和Hcs可减少快速抽动肌群，减少肌肉蛋白质合成，增加肌肉蛋白质降解。R76W和Δ130-136小鼠都表现出肌肉收缩力量减弱，并伴随着典型的快抽动肌肉的快慢纤维转变。体外实验结果进一步表明，R76W和Δ130136小鼠的原代成骨细胞条件培养液(PO CM)对C2C12成肌细胞的肌管形成有抑制作用。此外，转基因小鼠循环和PO CM中的前列腺素E_2(PGE_2)水平均显著降低。有趣的是，给转基因小鼠注射PGE2可以挽救快速抽动的肌肉质量和功能；然而，这对蛋白质的合成和降解几乎没有影响。这些发现表明了一种通道特异性反应：抑制骨细胞Cx43 HCS减少了快速抽动的骨骼肌质量，同时减少了蛋白质合成和增加了蛋白质降解。相反，阻断Cx43 GJS导致快速抽动骨骼肌收缩力量和肌肉生成减少，PGE2可部分解释测量到的差异。
Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.
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影响因子：
8.8
作者：
Kitase Y;Vallejo JA;Gutheil W;Vemula H;Jähn K;Yi J;Zhou J;Brotto M;Bonewald LF
通讯作者：
Bonewald LF
影响因子：
4.1
作者：
Bonewald L
通讯作者：
Bonewald L
骨细胞连接蛋白 43 通道影响骨折愈合
影响因子：
5.6
作者：
Chen, Yunhe;Chen, Meng;Xu, Huiyun
通讯作者：
Xu, Huiyun
影响因子：
3.3
作者：
Cherian, PP;Siller-Jackson, AJ;Jiang, JX
通讯作者：
Jiang, JX
影响因子：
4
作者：
Kawao, Naoyuki;Kaji, Hiroshi
通讯作者：
Kaji, Hiroshi