Figure 1.  Role of osteoblasts and osteoclasts in bone remodelling.
Bone mass is maintained by a balance between the activity of osteoblasts (right), which form bone, and osteoclasts (left), which break it down. Normally, bone formation and bone resorption are closely coupled processes involved in the normal remodelling of bone. Osteoblasts make bone by producing a matrix that then becomes mineralized. Osteoblasts also regulate osteoclast activity through expression of cytokines such as receptor activator of nuclear factor-κB ligand (RANKL), which activates osteoclast differentiation, and osteoprotegerin (OPG), which inhibits RANKL. Factors that are known to stimulate osteoblast proliferation or differentiation are bone morphogenetic protein (BMP), transforming growth factor-β (TGFβ), insulin-like growth factor (IGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and WNT. The WNT antagonist DKK blocks osteoblast proliferation. Osteoclasts are large multinucleate cells that break down bone and are responsible for bone resorption.

Figure 2.  Signal-transduction pathways that regulate osteoblast function.
Binding of bone morphogenetic protein (BMP) to its receptor induces the formation of a complex in which the type II BMP receptor phosphorylates and activates the type I BMP receptor. The type I BMP receptor then propagates its signal by phosphorylating the SMAD1 and SMAD5 proteins. Phosphorylation of the SMAD proteins leads to the upregulation of RUNX2 and osterix, two transcription factors that control osteogenesis. BMP2 was also shown to activate p38 mitogen-activated protein kinase (MAPK), leading to an increase in RUNX2 transcription. Similarly, TGFβ regulates RUNX2 transcription by phosphorylating SMAD2 and SMAD3 as well as by activating p38 MAPK. Fibroblast growth factors (FGFs) signal through a group of high-affinity transmembrane receptors (FGFR1 to FGFR4), which have intrinsic tyrosine kinase activities. Insulin-like growth factor 1 (IGF1) and endothelin-1 (ET1), which bind to the receptor tyrosine kinases IGF1R and G-protein-coupled receptor ET_A, respectively, have both been shown to activate the MAPK pathway in osteoblasts. Signal transduction from these growth factors results in the activation of RUNX2 and/or osterix. In osteoblasts, the interactions between FGF2 and its receptors induce dimerization and autophosphorylation of these receptors, which in turn activate p42/44 MAPK and protein kinase C (PKC). Activation of PKC leads to an increase in RUNX2 transcription, whereas phosphorylation and activation of p42/44 MAPK leads to RUNX2 protein phosphorylation and activation. Activation of RUNX2 and/or osterix leads to increased expression of osteoblast-specific genes, such as alkaline phosphatase and osteocalcin. This results in increased bone formation. The WNT proteins, on the other hand, interact with WNT receptor frizzled and co-receptor LRP5 or LRP6 to activate a signalling pathway that stabilizes cytoplamic β-catenin. Stabilized β-catenin is then translocated to the nucleus to regulate as-yet-unidentified genes that promote bone formation.

Figure 3.  Prostate cancer cell and osteoblast interaction.
Prostate cancer (PCa) cells influence bone homeostasis by secreting paracrine factors that regulate osteoblast proliferation or differentiation. These factors include bone morphogenetic protein (BMP), transforming growth factor-β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), endothelin-1 (ET1), the bone metastasis factor MDA-BF-1, urokinase-type plasminogen activator (uPA) and prostate-specific antigen (PSA). These factors have been shown to support osteoblast proliferation by exerting direct effects on osteoblasts (BMP, TGFβ, IGF, PDGF, VEGF, ET1, MDA-BF-1) or influence osteoblast proliferation by modifying growth factors present in the bone microenvironment (uPA and PSA). In addition, these growth factors modulate osteoblast function to promote deposition of new bone matrix. The newly formed bone has features of immature bone (woven bone) with collagen fibres arranged in irregular random arrays. Woven bone is eventually converted into lamellar bone, which is mature bone with collagen fibres arranged in lamellae. Osteoblasts also produce factors that stimulate proliferation of prostate cancer cells (green circles); these bone-derived factors have not yet been identified.