|Title:||Non-neuronal and non-enzymatic role of acetylcholinesterase in bone remodeling and disorder|
|Advisors:||Wen, Chunyi (BME)|
Zheng, Yongping (BME)
Acetylcholinesterase -- Therapeutic use
Hong Kong Polytechnic University -- Dissertations
|Department:||Department of Biomedical Engineering|
|Pages:||182 pages : color illustrations|
|Abstract:||Osteoporosis is a multifactor degenerative bone loss disease characterized by the uncoupling of bone formation and bone resorption. As one of the leading causes of disability and even death in the elderly, osteoporosis poses enormous societal burdens to the whole world. Although several FDA-approved drugs are available, osteoporotic fractures remain an unresolved problem.|
The positive correlation between Alzheimer's disease and osteoporosis has been noticed for a long time. Recently, the use of AChE inhibitors has been reported to associate with reduced risk of hip fractures, elevated healing of osteoporotic fractures, and decreased overall mortality in Alzheimer's disease patients. Meanwhile, it has been reported that the expression of AChE and other cholinergic components existed not only in the nervous system but also in the bone system. AChE and other cholinergic components have also been recently proposed to be correlated with the regulation of bone homeostasis. These cues indicate a possible role of AChE and its inhibitors in the treatment of osteoporosis.
The roles and the underlying mechanism of AChE, however, in osteoblast senescence and osteoclastogenesis under pathological conditions remain unclear. We aimed to determine the roles of AChE and its inhibitors in osteoblast senescence, osteoclastogenesis, and osteoblastosteoclasts crosstalk in osteoporosis development as well as the feasibility of employing AChE inhibitors for osteoporosis treatment.
In this study, we first demonstrated that the AChE expression increased during the natural aging process in the mice model. For the in vitro study, we found that osteoblasts could form an autocrine loop of AChE and amplify the senescence of osteoblast continuously. We firstly confirmed an upregulated expression of AChE with an increased level of p21 and p16INK4a in an H2O2-induced senescence model of osteoblastic cells. Moreover, with the incubation with recombinant AChE protein or heat-inactivated AChE protein, a higher level of early senescent marker p21 in osteoblastic cells was observed. Additionally, the treatment of dual-bind AChE inhibitor donepezil but not catalytic inhibitor galantamine could partly rescue the H2O2 induced senescence in osteoblasts.
We also found that AChE played an important role in regulating osteoclastogenesis. We first confirmed that the AChE secreted by senescent osteoblasts could trigger the migration of osteoclast precursors. Secondly, our results suggested that both intact AChE and heat-inactivated AChE (HAChE) protein could promote the adhesion of osteoclast precursors. Thirdly, AChE and HAChE treatments accelerated the process of osteoclast fusion. The expression of AChE was also elevated during osteoclastic differentiation. Reversely, we observed that genetic silence of AChE led to a lower differentiation ratio of osteoclasts. Moreover, dual binding AChE inhibitor donepezil but not catalytic AChE inhibitor galantamine suppressed osteoclastogenesis in vitro, further suggesting that the non-enzymatic function and peripheral anionic site of AChE got involved in the regulation of osteoclast differentiation.
To investigate the protective effect of AChE inhibitors for the treatment of osteoporosis, we used the OVX mice as an osteoporotic in vivo model. We demonstrated that the expression of AChE protein increased in OVX induced postmenopausal osteoporosis in vivo. The pharmaceutical inhibition of AChE could rescue postmenopausal bone loss in vivo. In particular, the BBB (blood-brain barrier)-impermeable AChE inhibitor ambenonium indicated a comparable rescue effect to BBB-permeable inhibitor donepezil, which suggested that targeting peripheral AChE protein could also rescue OVX-induced bone loss.
In short, with the aging and bone degeneration development, higher expression of AChE occurred in senescent osteoblasts and further accelerated osteoblast aging. The elevated AChE was deposited in the bone matrix and was released to the bone microenvironment during osteoclast-mediated bone resorption. These released AChE proteins stimulated increased osteoclastogenesis. This study, for the first time, implicated the roles of AChE, a hydrolytic enzyme of choline ester, in bone homeostasis and disease. AChE inhibitor donepezil could be an emerging drug for osteoporosis treatment. This study will lead to the discovery of dual-acting AChE inhibitors as an alternative for the treatment of osteoporosis, which will open a new avenue for osteoporosis treatment via repositioning the AChE inhibitors.
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