Circulating Osteoclast Precursors: A Mechanism and a Marker of Erosive Arthritis

Abstract

Genetic studies have demonstrated that osteoclasts are essential for focal erosion of bone and cartilage as a consequence of chronic pro-inflammatory cytokine production (TNF, IL-1) in inflammatory arthritis. In these inflamed joints, mature osteoclasts differentiate from circulating osteoclast precursors (OCPs) in response to local increased production of RANKL and pro-inflammatory cytokines. Once activated to resorb calcified matrix, these osteoclasts have a short lifespan (days), and must be continually replaced by bone marrow derived OCPs to achieve focal erosions. Therefore, the peripheral blood OCP frequency may directly determine the severity of bone erosion around inflamed joints. Based on the remarkable advances in our knowledge of osteoclast biology, investigators have been able to model the molecular events that control temporal and spatial regulation of osteoclastogenesis in vivo. Here we review the results of these pre-clinical and clinical studies and provide model of pathogenesis in which pro-inflammatory cytokines produced in the joint feedback on the bone marrow to produce and release elevated numbers of OCP into the circulation, which then home to the inflamed joint. Understanding the regulation of OCP generation and mobilization will provide a new strategy for development of drug targets in the treatment of inflammatory arthritis and other disorders associated with elevated peripheral OCP/myeloid progenitors.

NF-κB p50 and p52 Regulate Receptor Activator of NF-κB Ligand (RANKL) and Tumor Necrosis Factor-induced Osteoclast Precursor Differentiation by Activating c-Fos and NFATc1

“…These two cytokines can increase the expression of each other by accessory cells and of TNF by osteoclasts and their precursors (60,61). By this latter mechanism, TNF could amplify its osteoclastogenic effects in an autocrine auto-amplifying manner, setting up what we propose is an auto-amplifying cycle of increasing osteoclastogenesis whereby TNF induces more osteoclasts and their precursors, which produce more TNF to induce formation of more osteoclasts, and so on.…”

Th17 and Treg Cells in Bone Related Diseases

“…The co-stimulation by RANKL and M-CSF is essential for the differentiation of monocytes/macrophages into osteoclasts [32]. Aberrant regulation of osteoclast precursors (OCPs) generation, mobilization, differentiation, and activation by cytokines such as tumor necrosis factor (TNF) may have a major impact on the development and progression of inflammatory bone loss [33]. …”

Osteoclast precursors, RANKL/RANK, and immunology

“…OCPs are generated in the bone marrow, and following their mobilization, they are carried to diseased sites through the blood stream, where they give rise to osteoclasts to resorb bone and also function as effector cells to enhance the inflammatory process simultaneously. Thus, regulation of OCP generation, mobilization, differentiation, and activation may have a major impact on inflammatory bone loss (7).…”