TARGETING SIMIAN-VIRUS-40 T-ANTIGEN TO THE OSTEOCLAST IN TRANSGENIC MICE CAUSES OSTEOCLAST TUMORS AND TRANSFORMATION AND APOPTOSIS OF OSTEOCLASTS

Osteoclasts are terminally differentiated cells that express tartrate- resistant acid phosphatase (TRAP) at a higher level than other normal cells. Therefore, in an attempt to develop immortalized osteoclasts, w e produced two lines of transgenic mice in which expression of the sim ian virus 40 T antigen oncogene was targeted to osteoclasts using the TRAP gene promoter. Osteoclasts were increased in number in bones from both lines. More than 50% of them appeared morphologically transforme d, 2-5% were mitotic, but, unexpectedly, 5% were apoptotic. Osteoclast tumors were observed occasionally in one line of mice (line 4), and s heets of TRAP-positive cells (tumorlets) developed in most mice in bot h lines. Although cells isolated from these tumorlets formed multinucl eated TRAP-positive cells that resorbed bone in vitro, to date we have been unable to develop an immortalized osteoclast cell line from them . Osteoclasts from one line (line 5) had reduced ruffled border format ion and a higher level of T-antigen expression than osteoclasts in the other line (line 4), and these features were associated with the pres ence of osteopetrosis. However, osteoclasts from these osteopetrotic m ice and from line 4 mice resorbed bone normally when the mice were tre ated with interleukin-1. These findings indicate that T antigen can be targeted to osteoclasts in transgenic mice and causes osteoclast tran sformation, tumors, mitosis, and apoptosis. When T antigen is expresse d at high levels, functional impairment of osteoclasts can be detected . Furthermore, these results suggest that T antigen is insufficient on its own to immortalize cells in the osteoclast lineage.