Reactive oxygen species induce the association of SHP-1 with c-Src and the oxidation of both to enhance osteoclast survival.
Loss of ovarian function causes oxidative stress as well as bone loss. We hypothesized that reactive oxygen species (ROS) induced by the failure of ovarian function are responsible for the bone loss by increasing the number of osteoclasts (OC). We found that ROS enhanced OC survival via Src homology 2 domain-containing phosphatase-1 (SHP-1), c-Src, Akt, and ERK. ROS induced the association of SHP-1 with c-Src as well as the oxidation of c-Src and SHP-1. This resulted in inactivation of SHP-1 and activation of c-Src via phosphorylation of Tyr(416). Knockdown of c-Src or SHP-1 abolished the effect of ROS on OC survival. Moreover, downregulation of SHP-1 upregulated activation of c-Src, Akt, and ERK in the absence of any stimulus, suggesting that inactivation of SHP-1 is required for OC survival. We demonstrated that the association and oxidation of c-Src and SHP-1 by ROS are key steps in enhancing OC survival, which are responsible for increased bone loss when ovarian function ceases.
Department of Biological Sciences, University of Ulsan, Ulsan, South Korea; and.
Ke
K
Ke
Department of Biological Sciences, University of Ulsan, Ulsan, South Korea; and.
Ok-Joo
OJ
Sul
Department of Biological Sciences, University of Ulsan, Ulsan, South Korea; and.
Eun-Kyung
EK
Choi
Department of Biological Sciences, University of Ulsan, Ulsan, South Korea; and.
Ali M
AM
Safdar
Department of Endocrinology, Ulsan University Hospital, Ulsan, South Korea.
Eun-Sook
ES
Kim
Department of Biological Sciences, University of Ulsan, Ulsan, South Korea; and hschoi@mail.ulsan.ac.kr.
Hye-Seon
HS
Choi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology*; D010052:Ovariectomy; D010084:Oxidation-Reduction; D017698:Postmenopause / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055815:Young Adult; D019061:src-Family Kinases / Q000378:metabolism*
D017382:Reactive Oxygen Species; D019061:src-Family Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
Src homology 2 domain-containing phosphatase-1; c-Src; loss of ovarian function; osteoclast survival; reactive oxygen species