Bone as a Target Organ in Rheumatic Disease: Impact on Osteoclasts and Osteoblasts

Abstract

Dysregulated bone remodeling occurs when there is an imbalance between bone resorption and bone formation. In rheumatic diseases, including rheumatoid arthritis (RA) and seronegative spondyloarthritis, systemic and local factors disrupt the process of physiologic bone remodeling. Depending upon the local microenvironment, cell types, and local mechanical forces, inflammation results in very different effects on bone, promoting bone loss in the joints and in periarticular and systemic bone in RA and driving bone formation at enthesial and periosteal sites in diseases such as ankylosing spondylitis (AS), included within the classification of axial spondyloarthritis. There has been a great deal of interest in the role of osteoclasts in these processes and much has been learned over the past decade about osteoclast differentiation and function. It is now appreciated that osteoblast-mediated bone formation is also inhibited in the RA joint, limiting the repair of erosions. In contrast, osteoblasts function to produce new bone in AS. The Wnt and BMP signaling pathways have emerged as critical in the regulation of osteoblast function and the outcome for bone in rheumatic diseases, and these pathways have been implicated in both bone loss in RA and bone formation in AS. These pathways provide potential novel approaches for therapeutic intervention in diseases in which inflammation impacts bone.

Keywords: Ankylosing spondylitis; Bone erosions; Bone formation; Bone remodeling; DKK1; Entheses; IL-23; Inflammation; Osteoblast; Osteoclast; Rheumatoid arthritis; Sclerostin; Wnt; microRNAs.

Fig. 1

Stages of osteoblast differentiation. Osteoblasts are derived from mesenchymal stem cells. Wingless (WNT) and bone morphogenic protein (BMP) pathways promote their differentiation to mesenchymal stromal cells, in conjuction with Runx2, insulin-like growth factor (IGF) and parathyroid hormone (PTH). Activation of BMP signaling promotes Runx2 expression in stromal cells, leading to further differentiation to osteoprogenitors. Runx2 subsequently induces expression of the transcription factor osterix, with further differentiation to a mature osteoblast. These ultimately become embedded in bone matrix as terminally differentiated osteocytes

Fig. 2

Cell types and factors regulating bone in rheumatic disease. Resorption: The inflamed synovium/pannus produces several inflammatory mediators that enhance osteoclastogenesis and inhibit osteoblast maturation in the joint, leading to the development and persistence of articular bone erosions. These mediators promote the differentiation of osteoclast precursors to mature osteoclasts, in part by the upregulation of receptor activator of NF-κB ligand (RANKL). Anti-citrullinated protein antibodies (ACPAs) can also promote osteoclastogenesis by binding to macrophages and/or osteoclast precursor cells and inducing TNF production, thus enhancing cellular expansion and differentiation. Formation: Bone formation occurs through the action of mature osteoblasts that produce organic bone matrix and orchestrate bone mineralization. These derive from mesenchymal precursors, whose differentiation is inhibited by antagonists of the Wnt signaling pathway, including Dickkopf (DKK) and secreted frizzled-related protein (SFRP) family members, and sclerostin, derived from osteocytes embedded in bone matrix. Inflammatory mediators also induce the production of RANKL, and inhibit the production of osteoprotegerin (OPG) by stromal cells/ osteoblasts. Furthermore, microRNAs can regulate these processes at several levels