An osteoclastic protein-tyrosine phosphatase may play a role in differentiation and activity of human monocytic U-937 cell-derived, osteoclast-like cells

Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, and Departments of Medicine and Biochemistry, Loma Linda University, Loma Linda, California 92357 Submitted 10 July 2003 ; accepted in final form 20 May 2004 This study investigated if an osteoclastic protein-tyrosine phosphatase (PTP), PTP-oc, plays a role in the functional activity and differentiation of osteoclastic cells by determining the effects of overexpression of wild-type (WT)- or phosphatase-deficient (PD)-PTP-oc on bone resorption activity and differentiation of human promyelomonocytic U-937 cells, which could be induced to differentiate into "osteoclast-like" cells by phorbol ester/1,25(OH) 2 D 3 treatment. U-937 cells overexpressing WT- or PD-PTP-oc were produced with a transposon-based vector. The size and depth of resorption pits created by WT-PTP-oc-overexpressing osteoclast-like cells were greater, while those by PD-PTP-oc-overexpressing osteoclast-like cells were less, than those created by control osteoclast-like cells. Overexpression of WT-PTP-oc also enhanced, while overexpression of PD-PTP-oc suppressed, their differentiation into osteoclast-like cells. Overexpression of WT-PTP-oc increased apoptosis and proliferation of U-937 cells, and overexpression of PD-PTP-oc reduced cell proliferation. Cells overexpressing WT-PTP-oc has also led to greater c-Src and NF- activation, whereas cells overexpressing PD-PTP-oc resulted in less c-Src and NF- activation. c-Src activation and NF- activation each correlated with resorption activity and differentiation into osteoclast-like cells. In summary, these results show that 1 ) PTP-oc regulates both the activity and the differentiation of osteoclast-like cells derived from U-937 cells; 2 ) PTP-oc enzymatic activity is important to these processes; 3 ) high PTP-oc enzymatic activity caused an increase in U-937 cell apoptosis and proliferation, leading to no significant changes in the number of viable cells; and 4 ) some of the PTP-oc actions are mediated in part by the c-Src and/or NF- pathways. osteoclast; resorption; nuclear factor- ; c-Src Address for reprint requests and other correspondence: K.-H. W. Lau, Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial VA Medical Center, 11201 Benton St., Loma Linda, CA 92357 (E-mail: laub{at}lom.med.va.gov )