Gavali, S. and Gupta, M.K. and Daswani, B. and Wani, M.R. and Sirdeshmukh, R. and Ikram Khatkhatay, M. (2019) LYN, a key mediator in estrogen-dependent suppression of osteoclastdifferentiation, survival, and function. BBA Molecular Basis of Disease, 1865 (3). pp. 547-557. ISSN 2019 Mar 1;1865(3):547-557.

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Abstract

Estrogen insufficiency at menopause cause accelerated bone loss due to unwarranted differentiation and function of osteoclasts. Unraveling the underlying mechanism/s may identify mediators of estrogen action which can be targeted for improved management of osteoporosis. Towards this, we analyzed the effect of 17β-estradiol on the proteomes of differentiating human osteoclasts. The major proteomic changes observed included upregulation of LYN by estrogen. We, therefore, investigated the effect of estrogen on osteoclast differentiation, survival, and function in control and LYN knockdown conditions. In control condition, estrogen treatment increased the apoptosis rate and suppressed the calcium signaling by reducing the intracellular Ca2+ levels as well as expression and activation of NFATc1 and c-Src during differentiation, resulting in reduced osteoclastogenesis. These osteoclasts were smaller in size with reduced extent of multinuclearity and produced significantly low levels of bone resorbing enzymes. They also exhibited disrupted sealing zone formation with low podosome density, impaired cell polarization and reduced resorption of dentine slices. Interestingly, in LYN knockdown condition, estrogen failed to induce apoptosis and inhibit activation of NFATc1 and c-Src. Compared to effect of estrogen on osteoclast in control condition, LYN knockdown osteoclasts did not show reduction in production of bone resorbing enzymes and had defined sealing zone formation with high podosome density with no impairment in cell polarization. They resorbed significant area on dentine slices. Thus, the inhibitory action of estrogen on osteoclast was severely restrained in LYN knockdown condition, demonstrating the importance of LYN as a key mediator of the effect of estrogen on osteoclastogenesis.

Item Type:	Article
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	11 Feb 2020 08:54
Last Modified:	11 Feb 2020 08:54
URI:	http://nccs.sciencecentral.in/id/eprint/610

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