Li Shangfu, Yang Bu, Teguh Dian, Zhou Lin, Xu Jiake, Rong Limin
Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, TianHe Road 600, TianHe District, Guangzhou 510630, China.
Molecular Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, WA, Australia.
Int J Mol Sci. 2016 Oct 10;17(10):1683. doi: 10.3390/ijms17101683.
Osteoporosis and Alzheimer's disease (AD) are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (Aβ), one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having an activation effect on osteoclast (Bone 2014,61:164-75). However, the underlying molecular mechanisms remain unclear. Activation of NF-κB, extracellular signal-regulated kinase (ERK) phosphorylates, and calcium oscillation signaling pathways by receptor activator NF-κB ligand (RANKL) plays a pivotal role in osteoclast activation. Targeting this signaling to modulate osteoclast function has been a promising strategy for osteoclast-related diseases. In this study, we investigated the effects of Aβ on RANKL-induced osteoclast signaling pathways in vitro. In mouse bone marrow monocytes (BMMs), Aβ exerted no effect on RANKL-induced osteoclastogenesis but promoted osteoclastic bone resorption. In molecular levels, Aβ enhanced NF-κB activity and IκB-α degradation, activated ERK phosphorylation and stimulated calcium oscillation, thus leading to upregulation of NFAT-c1 expression during osteoclast activation. Taken together, our data demonstrate that Aβ enhances RANKL-induced osteoclast activation through IκB-α degradation, ERK phosphorylation, and calcium oscillation signaling pathways and that Aβ may be a promising agent in the treatment of osteoclast-related disease such as osteoporosis.
骨质疏松症和阿尔茨海默病（AD）是常见的慢性退行性疾病，与高龄密切相关。我们之前已经证明，淀粉样β肽（Aβ）作为AD的病理特征之一，除了对破骨细胞有激活作用外，还在骨质疏松骨标本中异常积聚（《骨》，2014年，61卷：164 - 75页）。然而，其潜在的分子机制仍不清楚。核因子κB（NF - κB）的激活、细胞外信号调节激酶（ERK）的磷酸化以及受体激活剂NF - κB配体（RANKL）介导的钙振荡信号通路在破骨细胞激活中起关键作用。针对该信号通路调节破骨细胞功能一直是治疗破骨细胞相关疾病的一种有前景的策略。在本研究中，我们在体外研究了Aβ对RANKL诱导的破骨细胞信号通路的影响。在小鼠骨髓单核细胞（BMMs）中，Aβ对RANKL诱导的破骨细胞生成没有影响，但促进了破骨细胞的骨吸收。在分子水平上，Aβ增强了NF - κB活性和IκB - α降解，激活了ERK磷酸化并刺激了钙振荡，从而导致破骨细胞激活过程中活化T细胞核因子c1（NFAT - c1）表达上调。综上所述，我们的数据表明，Aβ通过IκB - α降解、ERK磷酸化和钙振荡信号通路增强RANKL诱导的破骨细胞激活，并且Aβ可能是治疗骨质疏松症等破骨细胞相关疾病的一种有前景的药物。
