Osteoclasts are cells of haematopoietic origin that are uniquely specialized to degrade bone. myeloid cell differentiation during inflammation could be an important contributor to the differentiation of osteoclast populations and their associated pathologies. Understanding the dynamics of osteoclast differentiation in inflammatory arthritis is crucial for the development of therapeutic strategies for inflammatory joint disease in children and adults. Introduction A number of different forms of chronic arthritis in children and adults can result in erosive disease causing substantial morbiity. In adults these potentially destructive arthritides include rheumatoid arthritis (RA) ankylosing spondylitis and psoriatic arthritis (PsA). Bone erosions are observed in more than 45% of patients with Lithocholic acid early RA and PsA.1 2 In children erosive subtypes of arthritis include polyarticular juvenile idiopathic arthritis (JIA) extended oligoarticular Lithocholic acid arthritis systemic JIA and PsA. Although bone erosions occur in these childhood diseases the prevalence of this outcome is not well defined as imaging assessments in children are challenging owing to the unique features of the growing skeleton.3 Epidemiological immunogenetic and clinical lines of evidence indicate that the various forms of erosive arthritis have distinct aetiologies. Although many factors influence the initiation of musculoskeletal damage the mechanism of bone and joint destruction SAPK1 seems to represent in large part a final common pathway. This pathway relies on the differentiation and activation of osteoclasts the only specialized cells to resorb bone. Osteoclasts are terminally differentiated cells of the myeloid lineage and their precursors are mononuclear phagocytes. The regulation of their differentiation under physiological conditions has been extensively studied with genetic experiments in mice.4 However emerging evidence especially from primary human cell cultures suggests that inflammatory conditions give rise to alternative pathways of osteoclast differentiation and activation. These pathways are less-well-studied than the physiological pathway and involve a variety of cytokines as mediators and several cell types both as targets of these secreted factors and as participants in the cell-cell interactions that lead to differentiation of functional osteoclasts. The contribution of alternative pathways of osteoclast differentiation and Lithocholic acid activation to erosive potential in inflammatory arthritis is the subject of this Perspectives article. Physiological bone remodelling Physiological bone remodelling is orchestrated by two main cell types with opposing functions: osteoblasts which form new bone and osteoclasts which resorb damaged or old bone. Osteoblasts are derived from mesenchymal stem cell (MSC) progenitors which reside in the bone marrow close to haematopoietic stem cell (HSC) niches. This Lithocholic acid location enables MSCs to maintain bone marrow homeostasis and to regulate the maturation of both haematopoietic and non-haematopoietic cells. MSCs have broad potential and differentiate into cell types including osteoblasts osteocytes adipocytes and chondrocytes (reviewed in detail elsewhere5). Osteoclasts on the other hand are derived from bone-marrow HSCs which also have the capacity to differentiate into other cell types including macrophages and dendritic cells (DCs).6 Osteoclast differentiation The development of the mononuclear phagocyte system is controlled primarily by cytokines with macrophage colony-stimulating factor 1 (CSF-1 also Lithocholic acid known as M-CSF) as the principal regulator of lineage. CSF-1 signals through the tyrosine kinase receptor CSF-1R which is ubiquitously expressed during early myeloid lineage commitment and its expression is maintained by nearly all mononuclear phagocytic cells and by terminally differentiated osteoclasts highlighting the interdependence of these lineages.6 The differentiation of osteoclast precursors under physiological conditions is regulated by receptor activator of nuclear factor κB ligand (RANKL also known as TNF ligand superfamily member 11). RANKL-mediated osteoclast differentiation depends on receptor activator of nuclear factor κB (RANK; TNF receptor Lithocholic acid superfamily.