title: Non-Canonical (RANKL-Independent) Pathways of Osteoclast Differentiation and Their Role in Musculoskeletal Diseases.
abstract: Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, macrophages); in the canonical pathway of osteoclastogenesis, these cells fuse and differentiate to form specialised bone-resorbing osteoclasts in the presence of receptor activator for nuclear factor kappa B ligand (RANKL). Non-canonical pathways of osteoclastogenesis have been described in which several cytokines and growth factors are able to substitute for RANKL. These humoral factors can generally be divided into those which, like RANKL, are tumour necrosis family (TNF) superfamily members and those which are not; the former include TNFα lymphotoxin exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF); the latter include transforming growth factor beta (TGF-β), interleukin-6 (IL-6), IL-8, IL-11, nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and IGF-II. This review summarises the evidence for these RANKL substitutes in inducing osteoclast differentiation from tissue-derived and circulating mononuclear phagocytes. It also assesses the role these factors are likely to play in promoting the pathological bone resorption seen in many inflammatory and neoplastic lesions of bone and joint including rheumatoid arthritis, aseptic implant loosening and primary and secondary tumours of bone.
authors.affiliation: The Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Clinical Laboratory Services, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sabokbar
authors.affiliation: The Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Clinical Laboratory Services, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Mahoney
authors.affiliation: The Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Clinical Laboratory Services, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK.
authors.forename: F
authors.initials: F
authors.lastname: Hemingway
authors.affiliation: The Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Clinical Laboratory Services, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK. nick.athanasou@ndorms.ox.ac.uk.
authors.forename: N A
authors.initials: NA
authors.lastname: Athanasou
mesh_terms: D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D005810:Multigene Family; D009140:Musculoskeletal Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D048069:Tumor Necrosis Factors
keywords: Bone resorption; Cytokine; LIGHT; Osteoclast; RANKL; TNF