Smad2 and Smad3 expressed in skeletal muscle promote immobilization-induced bone atrophy in mice
Smad2 and Smad3 expressed in skeletal muscle promote immobilization-induced bone atrophy in mice
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骨骼肌中表达的 Smad2 和 Smad3 促进小鼠固定诱导的骨萎缩
DOI：
10.1016/j.bbrc.2021.10.043
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发表时间：
2021
影响因子：
3.1
通讯作者：
Miyamoto Takeshi
中科院分区：
文献类型：
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作者：
Umezu Taro;Nakamura Satoshi;Sato Yuiko;Kobayashi Tami;Ito Eri;Abe Takaya;Kaneko Mari;Nomura Masatoshi;Yoshimura Akihiko;Oya Akihito;Matsumoto Morio;Nakamura Masaya;Kanaji Arihiko;Miyamoto Takeshi
众所周知，骨骼肌通过肌肉与骨骼的相互作用来调节骨稳态，但控制这种活动的因素仍不清楚。在这里，我们新建立了Smad3-flox小鼠，然后通过将Smad3-flox与骨骼肌特异性Ckmm Cre和Smad2-flox小鼠杂交产生骨骼肌特异性Smad2/Smad3双条件敲除小鼠(DcKO)。我们发现，由于坐骨神经去神经支配而发生的固定诱导的腓肠肌萎缩在 DcKO 小鼠中受到部分但显着的抑制，这表明骨骼肌细胞固有的 Smad2/3 是固定诱导的肌肉萎缩所必需的。此外，坐骨神经去神经支配后观察到的胫骨萎缩在 DcKO 小鼠中得到部分但显着的抑制。野生型小鼠胫骨的骨形成率因固定而受到显着抑制，但在 DcKO 小鼠中抑制作用被消除。我们认为骨骼肌通过 Smad2/3 调节固定诱导的骨萎缩，而 Smad2/3 代表了预防固定诱导的骨和肌肉萎缩的潜在治疗靶点。
Skeletal muscle is known to regulate bone homeostasis through muscle-bone interaction, although factors that control this activity remain unclear. Here, we newly established Smad3-flox mice, and then generated skeletal muscle-specific Smad2/Smad3 double conditional knockout mice (DcKO) by crossing Smad3-flox with skeletal muscle-specific Ckmm Cre and Smad2-flox mice. We show that immobilization-induced gastrocnemius muscle atrophy occurring due to sciatic nerve denervation was partially but significantly inhibited in DcKO mice, suggesting that skeletal muscle cell-intrinsic Smad2/3 is required for immobilization-induced muscle atrophy. Also, tibial bone atrophy seen after sciatic nerve denervation was partially but significantly inhibited in DcKO mice. Bone formation rate in wild-type mouse tibia was significantly inhibited by immobilization, but inhibition was abrogated in DcKO mice. We propose that skeletal muscle regulates immobilization-induced bone atrophy via Smad2/3, and Smad2/3 represent potential therapeutic targets to prevent both immobilization-induced bone and muscle atrophy.