Mechanisms of palmitate-induced cell death in human osteoblasts

Author:

Gunaratnam Krishanthi1,Vidal Christopher1,Boadle Ross2,Thekkedam Chris1,Duque Gustavo1

Affiliation:

1. Ageing Bone Research Program, Sydney Medical School Nepean, The University of Sydney, Penrith, NSW 2750, Australia

2. Electron Microscope Laboratory, ICPMR and Westmead Research Hub, Westmead, NSW 2145, Australia

Abstract

Summary Lipotoxicity is an overload of lipids in non-adipose tissues that affects function and induces cell death. Lipotoxicity has been demonstrated in bone cells in vitro using osteoblasts and adipocytes in coculture. In this condition, lipotoxicity was induced by high levels of saturated fatty acids (mostly palmitate) secreted by cultured adipocytes acting in a paracrine manner. In the present study, we aimed to identify the underlying mechanisms of lipotoxicity in human osteoblasts. Palmitate induced autophagy in cultured osteoblasts, which was preceded by the activation of autophagosomes that surround palmitate droplets. Palmitate also induced apoptosis though the activation of the Fas/Jun kinase (JNK) apoptotic pathway. In addition, osteoblasts could be protected from lipotoxicity by inhibiting autophagy with the phosphoinositide kinase inhibitor 3-methyladenine or by inhibiting apoptosis with the JNK inhibitor SP600125. In summary, we have identified two major molecular mechanisms of lipotoxicity in osteoblasts and in doing so we have identified a new potential therapeutic approach to prevent osteoblast dysfunction and death, which are common features of age-related bone loss and osteoporosis.

Publisher

The Company of Biologists

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

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