ELSEVIER Journal of Orthopaedic Research 21 (2003) 62-72 zyxwv Journal of Ort hopaed ic Research www.elsevier.com/locate/orthres Differences in the cytokine profiles associated with prostate cancer cell induced osteoblastic and osteolytic lesions in bone Y. Lee a, E. Schwarz ’, M. Davies a, M. Jo a, J. Gates a, J. Wu a, X. Zhang a, J.R. Lieberman a,* zyxwv Department of Orthopaedic Surgery, UCLA School of Medicine, Los Angeles, CA, USA Depcirtment zyxwvutsrqp of Orthopaedic Surgery, Wnicersity of Rochester Medical Center, USA Received 6 December 2001; accepted 1 May 2002 zyxwv Abstract Prostate adenocarcinoma is associated with the formation of osteoblastic metastases in bone. It is hypothesized that osteocl- astogenesis is a critical component in the development of skeletal metastases. These findings, however, were generally noted in predominantly osteolytic lesions. The pathophysiology of osteoblastic lesions remains unknown but the type of bone lesion formed may be influenced by the cytokines produced by prostate tumors. To test this theory, we implanted PC-3 and LAPC-9 cells into the tibias of SCID mice. These mice were sacrificed at 1, 2,4, 6, and 8 weeks after implantation and histologic analysis was performed on these tibias. PCR analysis was also performed on bulk tumors. The results showed that the PC-3 implanted tibias developed pure osteolytic lesions while the LAPC-9 implanted tibias developed pure osteoblastic lesions on radiographs. Analysis of tibias after injection with PC-3 cells revealed progressive osteolytic lesions with abundant osteoclast activity at 2 weeks and destruction of the proximal tibia at 6 weeks after cell implantation. In contrast, the LAPC-9 cells formed osteoblastic lesions six weeks after cell injection. There were rare osteoclasts prior to the establishment of the osteoblastic lesions but greater osteoclast activity was noted with remodeling of the osteoblastic lesion 8 weeks after implantation of the tumor cells. PCR analysis revealed that PC-3 cells produced RANKL, IL-1, and TNF-a, which are associated with osteoclastogenesis. In contrast, LAPC-9 cells produced osteo- protegerin, which blocks osteoclast production and no detectable levels of RANKL or IL-1 and only minimal amounts of TNF-c( were noted. These cells secreted BMP-2, -4, -6, and IL-6, which are associated with bone formation. These results suggest that the role of the osteoclast in the development of a metastatic lesion is variable depending on the phenotype of the prostate cancer cells, and that tumor-induced osteolysis may not be required for osteoblastic metastases. zyxw 0 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. Keywords: Prostate cancer; Metastasis; Osteoblastic lesions; Osteoprotegerin: Cytokines Introduction Prostate cancer metastases to bone are associated with significant morbidity and mortality zyxwvuts [ 18,33,34]. The pathophysiology of the development of prostate cancer metastases to bone remains poorly understood. Under- standing the biological mechanism behind prostate cancer metastases to bone would enhance the develop- ment of regimens to treat this disease. One of the properties characteristic of prostate cancer is that metastases to bone produce pure osteoblastic *Corresponding author. Address: CHS 76-134, UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. Tel.: + 1-3 10-825-7687; fax: + 1-3 10-206-0063. E-mail address: jlieberman@mednet.ucla.edu (J.R. Lieberman). lesions [19,21,33,34,37]. In one series, the incidence of pure osteoblastic metastases was 95% while the re- maining 5% of the prostate metastases formed a mixed osteoblastic/osteolytic lesion late in the disease process [33,34,37]. Once prostate cancer cells deposit in bone, it is believed that reciprocal cellular interactions between prostate cancer cells and the bone stroma result in the proliferation of both prostate cancer and bone stromal cells. In vitro studies have shown that the paracrine factors produced by prostate cancer cells are mitogenic for osteoblasts and that factors produced by osteoblasts are chemotactic and mitogenic for prostate cancer cells [ 1,6,12,27,29,36]. However, the critical interplay be- tween prostate cancer cells, osteoblasts, bone stroma, and various cytokines and growth factors that produce osteoblastic lesions has yet to be defined. 0736-0266/03/$ - see front matter 0 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved PII: SO7 3 6- 0266( 02)O 0 09 5 - 5