## 4 Overview of Abnormal Bone Remodeling in MM and Bone Cancers  
Cancer in bone disrupts the balance between OBs and OCLs activities resulting in perturbation of bone remodeling, bone pain, fractures, and increased tumor growth. According with the seed-and-soil hypothesis proposed by [PERSON] in 1889, multiple interactions between tumor cells and the bone microenvironment are essential for the development of bone metastasis [20]. In particular, tumor cells possess adhesive molecules for the binding to stromal cells and bone matrix. This interplay induces the production by cancer cells of angiogenic and bone-resorbing factors that, in turn, increase cancer growth in bone. Moreover, numerous growth factors released during bone resorption (e.g., TGF-\(\beta\), BMP, FGF, calcium) make up the fertile soil needed for cancer cells growth [20]. In MM, the accumulation of malignant plasma cells (PCs) into the bone marrow (BM) disrupts the physiological bone remodeling process, ultimately leading to bone destruction [3]. The stimulation of bone-resorbing OCLs and the suppression of bone-forming OBs by MM occur either directly and through multiple cell-to-cell contact with bone microenvironment cells. At the same time, these alterations support the growth and survival of MM cells within the BM niche contributing to the vicious cycle of tumor growth and bone destruction. Cytokines and chemokines released either by MM cells and produced by stromal cells after physical interactions with MM cells are responsible for the abnormal bone remodeling in MM. Specifically, MM cells upregulate the expression of RANKL in BM stromal cells and decrease the release of OPG, thus supporting OCL recruitment [3; 21]. Moreover, MM patients show an increased RANKL/OPG ratio that correlates with the extent of bone disease [22; 23]. In addition to RANKL, other OCL-activating factors, such as chemokine (C-C motif) ligand (CCL)-3, interleukin (IL)-1, IL-3, IL-6, activin A, and TNF\(\alpha\), are upregulated by MM cells in BM microenvironment [24; 25; 26; 27; 28]. The reciprocal interplay between MM cells and stromal cells also hinders OB differentiation. MM cells reduce the activity of Runt-related transcription factor (Runx)-2 in human OB progenitors by cell-to-cell contact leading to an impaired OB differentiation [29]. Other factors, such as IL-7 and hepatocyte growth factor (HGF), were found to decrease Runx2 activity and characterize BM MM patients compared with controls. [30; 31]. Moreover, MM cells produce Wnt inhibitors Dkk-1, soluble fizzled-related protein (sFRP), and sclerostin, thus contributing to the inhibition of OB differentiation. In this regard, MM patients have a high level of Dkk-1, sFRP-2, and sFRP-3 in BM [32; 33; 34; 35; 36]. In bone metastasis of solid tumors, the BM microenvironment frames a pivotal role in controlling the survival of cancer cells. In prostate carcinoma, bone provides a series of adhesion and growth factors responsible for the growth and proliferation of cancer cells in the skeleton [37]. In particular, prostate carcinoma skeletal metastases are mainly characterized as osteoblastic lesions. In this case, cancer cells induce a series of bone remodeling alterations that increase OBs' activation and bone production. The increased OBs-mediated mineralization outbalances the induction of bone resorption resulting in the formation of osteoblastic lesions [37]. Many factors responsible for the formation of osteoblastic lesions have been identified. Among these, BMPs and endothelin directly stimulate the differentiation of OBs' precursors as well the production of OBs' specific proteins. Parathyroid hormone-related protein (PTHrP) reduces OBs' apoptosis [37]. In contrast, metastatic lesions characterizing breast cancer are predominantly osteolytic. Brest cancer cells produce PTHrP, which stimulate the production of RANKL by OBs and the subsequent increase in OCL activity and bone resorption [38].