PMID- 23050044 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20121011 LR - 20220410 IS - 1947-6027 (Electronic) IS - 1947-6019 (Print) IS - 1947-6019 (Linking) VI - 3 IP - 2 DP - 2012 Feb TI - Oncostatin m promotes mammary tumor metastasis to bone and osteolytic bone degradation. PG - 117-30 LID - 10.1177/1947601912458284 [doi] AB - Oncostatin M (OSM) is an interleukin-6 (IL-6) family cytokine that has been implicated in a number of biological processes including inflammation, hematopoiesis, immune responses, development, and bone homeostasis. Recent evidence suggests that OSM may promote breast tumor invasion and metastasis. We investigated the role of OSM in the formation of bone metastases in vivo using the 4T1.2 mouse mammary tumor model in which OSM expression was knocked down using shRNA (4T1.2-OSM). 4T1.2-OSM cells were injected orthotopically into Balb/c mice, resulting in a greater than 97% decrease in spontaneous metastasis to bone compared to control cells. Intratibial injection of these same 4T1.2-OSM cells also dramatically reduced the osteolytic destruction of trabecular bone volume compared to control cells. Furthermore, in a tumor resection model, mice bearing 4T1.2-OSM tumors showed an increase in survival by a median of 10 days. To investigate the specific cellular mechanisms important for OSM-induced osteolytic metastasis to bone, an in vitro model was developed using the RAW 264.7 preosteoclast cell line co-cultured with 4T1.2 mouse mammary tumor cells. Treatment of co-cultures with OSM resulted in a 3-fold induction of osteoclastogenesis using the TRAP assay. We identified several tumor cell-induced factors including vascular endothelial growth factor, IL-6, and a previously uncharacterized OSM-regulated bone metastasis factor, amphiregulin (AREG), which increased osteoclast differentiation by 4.5-fold. In addition, pretreatment of co-cultures with an anti-AREG neutralizing antibody completely reversed OSM-induced osteoclastogenesis. Our results suggest that one mechanism for OSM-induced osteoclast differentiation is via an AREG autocrine loop, resulting in decreased osteoprotegerin secretion by the 4T1.2 cells. These data provide evidence that OSM might be an important therapeutic target for the prevention of breast cancer metastasis to bone. FAU - Bolin, Celeste AU - Bolin C AD - Department of Biological Sciences, Boise State University, Boise, ID, USA. FAU - Tawara, Ken AU - Tawara K FAU - Sutherland, Caleb AU - Sutherland C FAU - Redshaw, Jeff AU - Redshaw J FAU - Aranda, Patrick AU - Aranda P FAU - Moselhy, Jim AU - Moselhy J FAU - Anderson, Robin AU - Anderson R FAU - Jorcyk, Cheryl L AU - Jorcyk CL LA - eng GR - P20 RR016454/RR/NCRR NIH HHS/United States GR - P30 AR057235/AR/NIAMS NIH HHS/United States PT - Journal Article PL - United States TA - Genes Cancer JT - Genes & cancer JID - 101516546 PMC - PMC3463924 OTO - NOTNLM OT - OSM OT - bone metastasis OT - breast cancer OT - oncostatin M OT - osteoclastogenesis OT - osteolysis COIS- Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2012/10/11 06:00 MHDA- 2012/10/11 06:01 PMCR- 2012/02/01 CRDT- 2012/10/11 06:00 PHST- 2012/04/26 00:00 [received] PHST- 2012/07/25 00:00 [accepted] PHST- 2012/10/11 06:00 [entrez] PHST- 2012/10/11 06:00 [pubmed] PHST- 2012/10/11 06:01 [medline] PHST- 2012/02/01 00:00 [pmc-release] AID - 10.1177_1947601912458284 [pii] AID - 10.1177/1947601912458284 [doi] PST - ppublish SO - Genes Cancer. 2012 Feb;3(2):117-30. doi: 10.1177/1947601912458284.