The Role of the BMP Signaling Antagonist Noggin in the Development of Prostate Cancer Osteolytic Bone Metastasis Chiara Secondini, Antoinette Wetterwald, Ruth Schwaninger, George N. Thalmann, Marco G. Cecchini* Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland Abstract Members of the BMP and Wnt protein families play a relevant role in physiologic and pathologic bone turnover. Extracellular antagonists are crucial for the modulation of their activity. Lack of expression of the BMP antagonist noggin by osteoinductive, carcinoma-derived cell lines is a determinant of the osteoblast response induced by their bone metastases. In contrast, osteolytic, carcinoma-derived cell lines express noggin constitutively. We hypothesized that cancer cell-derived noggin may contribute to the pathogenesis of osteolytic bone metastasis of solid cancers by repressing bone formation. Intra-osseous xenografts of PC-3 prostate cancer cells induced osteolytic lesions characterized not only by enhanced osteoclast-mediated bone resorption, but also by decreased osteoblast-mediated bone formation. Therefore, in this model, uncoupling of the bone remodeling process contributes to osteolysis. Bone formation was preserved in the osteolytic lesions induced by noggin-silenced PC-3 cells, suggesting that cancer cell-derived noggin interferes with physiologic bone coupling. Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity. This investigation provides new evidence for a model of osteolytic bone metastasis where constitutive secretion of noggin by cancer cells mediates inhibition of bone formation, thereby preventing repair of osteolytic lesions generated by an excess of osteoclast-mediated bone resorption. Therefore, noggin suppression may be a novel strategy for the treatment of osteolytic bone metastases. Citation: Secondini C, Wetterwald A, Schwaninger R, Thalmann GN, Cecchini MG (2011) The Role of the BMP Signaling Antagonist Noggin in the Development of Prostate Cancer Osteolytic Bone Metastasis. PLoS ONE 6(1): e16078. doi:10.1371/journal.pone.0016078 Editor: Chad Creighton, Baylor College of Medicine, United States of America Received September 13, 2010; Accepted December 6, 2010; Published January 13, 2011 Copyright: 2011 Secondini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the European Commission (CANCURE-2006-020970 and PRIMA-504587) and from the Swiss National Foundation (3200-068409.02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: marco.cecchini@dkf.unibe.ch Introduction Skeletal metastasis is a common clinical manifestation in advanced-stage patients suffering from prostate cancer (CaP) [1,2] and mammary cancer (CaM) [3]. Bone metastases are the most important cause of morbidity in these patients, with pain and complications, including pathological fractures, spinal cord and nerve compression requiring analgesia, irradiation and orthopedic surgery, all associated with substantial costs [4]. At the metastatic site, tumor cells perturb the physiological bone homeostasis controlled by osteoblasts and osteoclasts. CaM bone metastases tend to elicit an osteolytic response, whereas CaP metastases are prevalently associated with an osteosclerotic reaction [5,6]. Both types of lesions compromise the skeletal integrity and eventually lead to pathological fractures. The exact mechanisms determining the osteolytic and osteo- sclerotic lesions in bone metastases are not clearly defined yet. The prevailing concept indicates that cancer cells secrete an excess of paracrine factors stimulating directly or indirectly osteoclast or osteoblast recruitment, thereby leading to unbalanced excess of bone resorption or formation, respectively [7,8]. It is widely accepted that the osteolytic reaction in bone metastasis results from an excess of osteoclast-mediated bone resorption. Cancer cells release paradigmatic ‘‘osteolytic’’ cyto- kines, such as parathyroid hormone-related protein (PTHrP), receptor activator of NF-B ligand (RANKL), interleukin-8 (IL-8) and colony stimulating factor-1 (CSF-1), directly or indirectly responsible for the increase in osteoclast recruitment, activity and survival. Subsequent release of growth factors from the bone matrix fuels cancer cell growth, which in turn further stimulates bone resorption, thus perpetuating the process and establishing a ‘‘vicious cycle’’ [5,9]. This hypothesis provides the rationale for inhibition of bone resorption as therapeutic interference with growth progression in osteolytic bone metastasis. However, pharmacologic inhibition of bone resorption has only a minimal or no positive impact on the healing of osteolytic lesions [10]. This strongly suggests that, besides an increase in osteoclast-mediated bone resorption, other mechanism(s) contribute to osteolysis. The osteolytic lesion in multiple myeloma (MM) is not only the result of an osteoclast-mediated increase in bone resorption [11], but also of an uncoupling of the bone remodeling process determined by a decrease in osteoblast-mediated bone formation [12,13]. Several antagonists of the Wingless (Wnt) signaling pathway, such as Dickkopf-1 (Dkk-1), secreted Frizzled-related protein (sFRP) -1 and -2, are over-expressed by MM cells and may contribute to the inhibition of Wnt-mediated osteoblast recruit- ment and, therefore, to repression of bone formation [11,14,15]. This view is further corroborated by experimental evidence PLoS ONE | www.plosone.org 1 January 2011 | Volume 6 | Issue 1 | e16078