Moonga B S, Dempster D W
Regional Bone Center, New York State Department of Health, Helen Hayes Hospital, Route 9W, West Haverstraw, NY 10993, USA.
Exp Physiol. 1998 Nov;83(6):717-25. doi: 10.1113/expphysiol.1998.sp004153.
The intracellular mechanisms responsible for inhibition of osteoclast activity are of significant interest in the search for more effective ways of managing bone diseases associated with enhanced bone resorption. Previous studies have suggested that the protein kinase C (PKC) pathway is an important inhibitory second messenger in osteoclasts. We, therefore, investigated the effects of the synthetic peptide fragments, PKC(530-558) and (19-36), which correspond to parts of the catalytic and regulatory domains of PKC, on the activity of isolated osteoclasts. These fragments have been shown to activate and inhibit PKC, respectively, in biochemical studies employing isolated rat brain PKC, but have rarely been employed in studies of cellular activity. PKC(19-36), an enzyme inhibitor (PKC-I), had no effect by itself on osteoclastic bone resorption. However, PKC(530-558), a PKC activator (PKC-A), caused a dose-responsive inhibition of bone resorption, which was accompanied by a rapid and distinctive change in osteoclast morphology. This effect was reversible: (a) upon removal of PKC-A, (b) upon continuous exposure to this fragment for more than 36 h, or (c) in the presence of PKC-I. In conclusion, a short synthetic peptide fragment of PKC (PKC-A) significantly inhibits osteoclastic bone resorption; this, together with the fact that the inhibitory effect is abolished in the presence of PKC-I, provides further evidence for an important physiological role for the PKC pathway in the regulation of osteoclast activity. Selective activation of this pathway may have important therapeutic implications for the management of bone diseases associated with enhanced resorption.
在寻找更有效治疗与骨吸收增强相关骨疾病的方法时，负责抑制破骨细胞活性的细胞内机制备受关注。先前的研究表明，蛋白激酶C（PKC）信号通路是破骨细胞中重要的抑制性第二信使。因此，我们研究了合成肽片段PKC(530 - 558)和(19 - 36)对分离破骨细胞活性的影响，这两个片段分别对应PKC催化域和调节域的部分区域。在使用分离的大鼠脑PKC进行的生化研究中，这些片段已分别显示出激活和抑制PKC的作用，但很少用于细胞活性研究。酶抑制剂PKC(19 - 36)（PKC - I）本身对破骨细胞骨吸收没有影响。然而，PKC激活剂PKC(530 - 558)（PKC - A）引起了骨吸收的剂量依赖性抑制，并伴随着破骨细胞形态的快速且显著变化。这种作用是可逆的：（a）去除PKC - A后；（b）持续暴露于该片段超过36小时后；或（c）在PKC - I存在的情况下。总之，PKC的一个短合成肽片段（PKC - A）显著抑制破骨细胞骨吸收；这一点，连同在PKC - I存在时抑制作用消失这一事实，为PKC信号通路在调节破骨细胞活性中的重要生理作用提供了进一步证据。该信号通路的选择性激活可能对治疗与吸收增强相关的骨疾病具有重要的治疗意义。
