Introduction Bone is a very
Bone is a very dynamic tissue resulting from coordinated phases of formation and resorption called bone remodelling. Additional to its role in phosphocalcic homoeostasis, bone remodelling process is necessary for bone growth, for renewal of cellular and extracellular matrix components to adapt bone organisation to the various biological and mechanical constraints [1–3]. Bone remodelling then leads to the renewal of around 10% of total bone mass each year in human. This metabolic process is based on a molecular crosstalk occurring between osteoblasts involved in bone apposition and osteoclasts specialized in bone resorption. Osteoclasts are multinucleated thyrotropin receptor that originated from hematopoietic stem cells [4–6] whereas osteoblasts are derived from bone marrow mesenchymal stem cells [3,7,8]. Osteoblasts control osteoclast differentiation and activation through a very complex network of soluble factors which act in combination with various hormones produced by endocrine system even if contacts between both cell types also strongly contribute to full activation of osteoclasts [9,10]. Reciprocity between osteoblasts and osteoclasts can be observed as shown by bidirectional signalling limiting osteoclast activities and stimulating osteoblast differentiation .
Bone remodelling can be dysregulated by oncologic events originated from bone cells (primary bone tumours: osteosarcoma, chondrosarcoma, Ewing\'s sarcoma, etc.) or from nonosseous origins (bone metastases). Large series revealed that around 0.2% of all neoplasms are bone sarcomas and two new primary bone tumours arise per 100,000 persons a year . Bone tissue is then the most frequent site of their first relapse and consequently, the incidence of bone metastases is relatively high and is dependent on the cancer cell types (i.e. in 70–80% of patients with breast or prostate cancer, in 40% of patients with lung metastases or with kidney cancer). Bone metastases are frequently associated with numerous clinical complications named skeletal-related events (SREs) and have a strong deleterious impact on the quality of life. SREs include pathological fractures or spinal cord compression and exacerbated bone pains. All bone tumours disrupt the equilibrium between bone apposition and bone resorption leading to the first stop of the tumour development to an osteolytic process followed or not by bone forming lesions. Soluble mediators stored initially into the bone matrix contribute in turn to stimulate the tumour growth and to maintain the vicious cycle between bone and tumour cells . The loss of equilibrium between bone formation and degradation combined with an osteomimetism behaviour of cancer cells (cancer cells acquire bone-like properties) explains the diversity of histological features (osteolytic or bone forming tumours) of bone metastases . Additionally, the modulation of bone micro-environment (“niche” concept) by cancer cells is beneficial for their proliferation and also contributes to the drug resistance patterns .
In the late 1990s, two research groups in Japan and in USA have identified a truncated TNF receptor-like molecule (named OPG for osteoprotegerin, TNFRSF11B) inducing marked osteopetrosis phenotype when overexpressed in transgenic mice [16,17]. One year later, RANKL (Receptor Activator of Nuclear Factor kB Ligand or TNFSF11) has been identified as a ligand for OPG [18,19]. In a few years, OPG/RANKL couple became the principal system regulating osteoclastogenesis and bone resorption and has impressively stimulated the development of OPG/RANKL targeting agents for the treatment of osteolytic disorders in oncologic contexts or not competing with bisphosphonates, a well admitted drug class for the treatment of bone loss [13,19–23].
OPG, RANK and RANKL are key protagonists controlling osteoclast biology and bone remodelling The critical function of OPG in osteoclastogenesis has been initially revealed by the osteopetrotic phenotype of mice overexpressing it [18,19]. In contrast, OPG deficient mice exhibit osteoporotic phenotype which is totally reversed by administration of recombinant OPG . RANKL has been identified as the main ligand of OPG known to bind RANK (TNFRSF11A), a transmembrane receptor of the TNFR superfamily . RANKL transgenic mice and RANKL knockout mice are respectively osteoporotic and osteopetrotic (Fig. 1). In fact, membrane and soluble RANKL produced by osteoblasts interact with RANK expressed on monocyte lineage and osteoclast precursors, induces osteoclast differentiation and consequently activates bone resorption [23, Fig. 1]. Discovery of the RANK/RANKL signalling pathway through NFkB in the osteoclast has clearly provided new insights into the mechanisms of osteoclastogenesis and how hormonal networks impact bone remodelling [23–26]. OPG is the third protagonists and acts as a decoy receptor, binds to RANKL, inhibits RANK–RANKL interactions and in fine is a strong anti-resorptive agent. The balance between bone resorption and bone apposition consequently depends on the ratio OPG/RANKL (Fig. 1). For instance, the relative equilibrium between OPG and RANKL levels results in a stable bone mass, and in contrast for instance to RANKL knockout where bone remodelling is in favour of excessive bone formation due a marked reduction of osteoclastogenesis (Fig. 1). Similarly, a clear relationship has been established between RANKL/OPG ratio and the severity of osteolysis in oncologic diseases as in benign diseases . It is now admitted that RANKL is absolutely required for osteoclastogenesis in vivo even if RANKL can be substituted in vitro by other ligands such as TNFα . As the other TNF members, OPG, RANK and RANKL exhibit very complex stoichiometric characteristics. Indeed, OPG is a dimeric molecule, but it can even act as a monomer and RANL and RANK are homotrimeric complexes [20,28–30]. Additionally, OPG biology is more complex than those initially described and possesses numerous ligands such as other TNF Related Apoptosis Inducing Ligand (TRAIL) , proteoglycans  and glycosaminoglycans [33,34], von Willebrand factor , complex VIII  which modulate its own activity.