Bisphosphonates inhibit phosphorylation of signal transducer and activator of transcription 3 and expression of suppressor of cytokine signaling 3: implications for their effects on innate immune function and osteoclastogenesis.
OBJECTIVE
This study tested the effects of bisphosphonates (BPs) on the suppressor of cytokine signaling 3 (SOCS3) protein in macrophages. SOCS3 has been shown to regulate cell differentiation and survival; however, its potential role in mediating the effects of BPs has not been explored.


METHODS
The cell viability of murine RAW 267.4 macrophages was assessed after culturing with control medium or media containing increasing concentrations of 2 BPs (ibandronate or clodronate) for 24, 48, and 72 hours. The phosphorylation status of signal transducer and activator of transcription 3 (STAT3) and the expression of SOCS3 protein levels were determined by Western blot analysis.


RESULTS
In control cultures, STAT3 phosphorylation and STAT3 and SOCS3 protein levels increased within 5 minutes after the addition of fresh medium. This increase was inhibited in cultures treated with both BPs. Macrophage cell viability also decreased after BP treatment.


CONCLUSIONS
These data demonstrate that, in addition to their effects on macrophage viability, BPs can decrease STAT3 and SOCS3 expression, which are important modulators of immune responses and bone homeostasis.
Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, Texas 75246, USA. jreuben@bcd.tamhsc.edu
Jayne S
JS
Reuben
Laura
L
Dinh
Jane
J
Lee
Jonathan
J
Stateson
Harold
H
Kamara
Lilin
L
Xiang
Lynne A
LA
Opperman
D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000077557:Ibandronic Acid; D007113:Immunity, Innate / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000187:drug effects* / Q000378:metabolism
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004002:Clodronic Acid; D000077557:Ibandronic Acid