Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
J Orthop Res. 2012 Dec;30(12):1979-84. doi: 10.1002/jor.22172. Epub 2012 Jun 13.
Aging demonstrates deleterious effects upon the skeleton which can predispose an individual to osteoporosis and related fractures. Despite the well-documented evidence that aging decreases bone formation, there remains little understanding whereby cellular aging alters skeletal homeostasis. We, and others, have previously demonstrated that gap junctions--membrane-spanning channels that allow direct cell-to-cell conductance of small signaling molecules--are critically involved in osteoblast differentiation and skeletal homeostasis. We examined whether the capacity of rat osteoblastic cells to form gap junctions and respond to known modulators of gap junction intercellular communication (GJIC) was dependent on the age of the animal from which they were isolated. We observed no effect of age upon osteoblastic Cx43 mRNA, protein or GJIC. We also examined age-related changes in PTH-stimulated GJIC. PTH demonstrated age-dependent effects upon GJIC: Osteoblastic cells from young rats increased GJIC in response to PTH, whereas there was no change in GJIC in response to PTH in osteoblastic cells from mature or old rats. PTH-stimulated GJIC occurred independently of changes in Cx43 mRNA or protein expression. Cholera toxin significantly increased GJIC in osteoblastic cells from young rats compared to those from mature and old rats. These data demonstrate an age-related impairment in the capacity of osteoblastic cells to generate functional gap junctions in response to PTH, and suggest that an age-related defect in G protein-coupled adenylate cyclase activity at least partially contributes to decreased PTH-stimulated GJIC.
衰老是骨骼产生有害影响的表现，这可能使个体易患骨质疏松症和相关骨折。尽管有大量文献证明衰老会降低骨形成，但对于细胞衰老如何改变骨骼内稳态的理解仍然很少。我们和其他人之前已经证明，缝隙连接——允许小分子信号分子直接细胞间传导的跨膜通道——在成骨细胞分化和骨骼内稳态中起着至关重要的作用。我们研究了大鼠成骨细胞形成缝隙连接的能力以及对已知缝隙连接细胞间通讯（GJIC）调节剂的反应是否取决于它们分离的动物的年龄。我们没有观察到年龄对成骨细胞 Cx43mRNA、蛋白或 GJIC 的影响。我们还检查了与年龄相关的甲状旁腺素刺激的 GJIC 变化。甲状旁腺素对 GJIC 表现出年龄依赖性效应：来自年轻大鼠的成骨细胞对甲状旁腺素有反应性增加 GJIC，而来自成熟或老年大鼠的成骨细胞对甲状旁腺素的 GJIC 没有变化。甲状旁腺素刺激的 GJIC 发生与 Cx43mRNA 或蛋白表达的变化无关。霍乱毒素显著增加了来自年轻大鼠的成骨细胞的 GJIC，与来自成熟和老年大鼠的成骨细胞相比。这些数据表明，成骨细胞产生功能性缝隙连接以响应甲状旁腺素的能力存在与年龄相关的损害，并表明 G 蛋白偶联腺苷酸环化酶活性与年龄相关的缺陷至少部分导致甲状旁腺素刺激的 GJIC 减少。
