A potential osteoporosis target in the FAS ligand/FAS pathway of osteoblast to osteoclast signaling

One of the pivotal factors in the health and maintenance of dense bone is the coordinated activity of osteoblasts and osteoclasts. Research scientists are developing an enormous knowledge base about the signaling that occurs between these two cell types with the goal of understanding the bone microenvironment under normal as well as resorptive disease states. This knowledge base has already led to the development of successful therapies for osteoporosis. The monoclonal antibody to receptor activator of nuclear factor-κB ligand (RANKL), known as Prolia^® (denosumab), is a recent example. RANKL is a cytokine expressed on the surface of the osteoblast in response to bone resorption cues like 1α,25-dihydroxyvitamin D3, parathyroid hormone (PTH), prostaglandin E₂ (PGE₂), and interleukin 11 (IL-11). A second cytokine, macrophage colony-stimulating factor (M-CSF), is released by the osteoblast on a continual basis with both cytokines promoting differentiation of osteoclast precursors. The osteoclast precursors express receptors for the two cytokines, c-Fms (M-CSF receptor) and RANK (RANKL receptor). Another ligand for c-Fms is IL-34, expressed primarily by splenic red pulp, which appears to act in concert with M-CSF and RANKL. Osteoblasts express a third factor which is a soluble tumor necrosis factor (TNF) receptor family member, osteoprotegrin (OPG), that serves as a “decoy” receptor for RANKL and thereby blocks RANKL-RANK binding to inhibit osteoclastogenesis. A construct of OPG in which the heparin-binding and death homology domains are removed and the remaining peptide is fused to the F_c domain of the human immunoglobulin G1 (IgG1) is used for experimental therapeutic purposes. The resulting fusion protein construct is called OPG-F_c, and it neutralizes RANKL. In a study of ovariectomized (OVX) rats, the combined use of OPG-F_c and alendronate (a commonly used bisphosphonate) significantly increased the mechanical strength properties of femurs and lumbar vertebrae bodies compared to treatment with either OPG-F_c or alendronate alone.