Osteosarcoma is a malignant bone tumor that commonly occurs in the pediatric population. Despite the use of chemotherapy and surgery

metastasis remains to be the leading cause of death in patients with osteosarcoma. We have previously reported that cytoplasmic mislocalization of p27 is associated with a poor outcome in osteosarcoma. In this study

we further show that lysyl oxidase (LOX) expression was associated with p27 mislocalization. LOX is an enigmatic molecule that acts as a tumor suppressor or a metastatic promoter; however

its role in osteosarcoma is still unclear. Hence

we performed both

in vitro

and

in vivo

analyses to dissect the role of LOX in osteosarcoma. The result of our survival analysis indicated that LOX expression significantly correlated with a poor outcome in osteosarcoma with or without controlling for the initial metastasis status (

P

<

 0.05). Functionally

we found that higher LOX expression promoted osteosarcoma cell proliferation

migration

and invasiveness

in vitro

and produced a higher number of mice with pulmonary metastases in an orthotopic xenograft mouse model. Mechanistically

phospho-FAK was increased in osteosarcoma cells with high LOX expression. Our results further showed that FAK inhibition significantly reduced tumor cell proliferation and migration

in vitro

as well as LOX-mediated metastasis in mice. Together

our findings suggest that there is a novel link between p27 mislocalization and LOX expression. LOX plays a pivotal role in osteosarcoma metastasis by upregulating FAK phosphorylation. FAK inhibition may constitute a promising therapeutic strategy to reduce the development of metastasis in osteosarcoma with LOX overexpression.