3). The other critical function of CCN2 is exerted under the interaction with extracellular matrix (ECM) molecules and cell adhesion molecules. By interacting with integrins, functions and other proteins and proteoglycans, CCN2 may promote adhesion and migration of osteoclast precursor cells and stimulate osteoclast formation and activation (Fig. 3). CCN2 may be an integrator/modulator of extracellular information and appears to allow the establishment and progression

of the tumor angiogenesis and bone destruction within the skeleton [78], [79] and [80] (Figure 3 and Figure 4). Suppression of bone-lesion development and limiting the progression of an established bone metastasis should be the primary goals of treating metastatic bone disease. Osteoclastic activity is the major contributor learn more to cancer-induced bone disease, and this cell type is an ideal target for therapies. For

instance, bisphosphonates have been widely and successfully used for the treatment of bone metastases in breast cancer and multiple myeloma patients [81], [82], [83] and [84], as they block not only bone resorption but also tumor-cell mitosis and additionally stimulate tumor-cell apoptosis [85]. The OPG/RANK/RANKL pathway offers multiple molecular checkpoints for therapeutic targeting of osteolytic MAPK Inhibitor Library metastases [86] and [87]. In a randomized, double-blind, phase-I clinical trial, a single subcutaneous dose of the recombinant OPG construct AMGN-0007 was effective in suppressing bone resorption in breast cancer patients with established skeletal metastasis [88]. Although AMGN-0007 had favorable pharmacokinetic and pharmacodynamic properties in the cancer patient population, one potential risk with a recombinant OPG molecule would be the generation

of old antibody titers against the endogenous OPG protein. RANKL inhibitor, denosumab (formerly AMG 162), has also been developed and is being tested in the clinic. Denosumab is a fully human monoclonal antibody against RANKL. Phase-I and -II clinical trials have shown that denosumab suppressed bone resorption in patients with malignant bone disease stemming from multiple myeloma, prostate, or breast cancer [89], [90] and [91]. Denosumab was generally well tolerated in those trials. No related serious adverse events occurred. Furthermore, no patient had detectable anti-denosumab antibodies. Another method to target RANKL includes an osteoprotegerin-like peptidomimetic (OP3-4), which was demonstrated to be capable of inhibiting myeloma bone disease in vivo model [92]. No clinical results using these latter strategies have been presented to date. PTHrP antibodies neutralize PTHrP and vitamin-D analogues and decrease PTHrP production [93]. PTHrP neutralizing antibodies are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and those of bone metastasis [94] and [95].