Mediators of inflammation and bone remodeling in rheumatic disease

Abstract

Remodeling of bone is a continuous process that occurs throughout life. Under normal physiologic conditions, bone-resorbing osteoclasts and bone-forming osteoblasts are tightly coupled and regulated to ensure proper balance, such that there is no net change in bone mass. However, inflammation perturbs normal bone homeostasis. The impact of inflammation on bone is dependent upon the anatomic site affected, cell types, factors and cytokines present in the local microenvironment, and local mechanical forces. Cytokines are central to the pathogenesis of inflammation-induced bone loss and contribute to the uncoupling of osteoclast-mediated bone resorption and osteoblast-mediated bone formation, thereby disrupting normal remodeling. In this review, we will discuss the effects of cytokines on bone in two settings, rheumatoid arthritis and spondyloarthritis, a disease category that includes ankylosing spondylitis, psoriatic arthritis, reactive arthritis, inflammatory bowel disease, and juvenile onset spondyloarthropathy. The outcome for bone in these disease settings is quite different, and an understanding of the pathogenic mechanisms leading to the net impact on bone has been essential in developing new therapeutic approaches to bone health in these diseases.

Keywords: Cytokines; Inflammation; Osteoblasts; Osteoclasts; Rheumatoid arthritis; Spondyloarthritis.

Fig. 1

Selected factors involved in the differentiation of osteoclasts and osteoblasts. Membrane-bound and soluble RANKL expressed by synovial fibroblasts and osteoblasts bind to the RANK receptor, located on osteoclast precursor cells, to promote osteoclastogenesis, resulting in mature osteoclasts that erode bone. IL-18 and other factors, including IL-33 and type I interferons, inhibit osteoclast differentiation by diverting the osteoclast precursor cells towards differentiation to dendritic cells. BMP signaling ligands BMP-2, -4, -7, among others, promote the differentiation of osteoblasts from mesenchymal precursor cells. Antagonists of the Wnt signaling pathway, including DKK-1, sFRP family members and sclerostin, inhibit osteoblast differentiation through inhibition of Wnt signaling, while BMP-3 is a negative regulator of the BMP pathway. Many miRNAs can also affect osteoblast differentiation. Among them, miR-335 inhibits DKK-1 to promote Wnt signaling and osteoblast differentiation, and miR-29b is maximally expressed during the mineralization stage of bone formation, and promotes osteogenesis.

Fig. 2

Major factors involved in new bone formation in SpA. TGF-β, IL-6 and IL-23 promote the differentiation of Th17 cells from naïve T cells. Th17 cells secrete pro-inflammatory cytokines, including IL-17 and IL-22 that generate inflammation at peripheral and axial enthesial sites. IL-23 induces expression of BMP-7 within the enthesis to promote osteoblast differentiation and function. IL-22 induces pro-osteogenic factors to also promote osteoblast differentiation and function. Decreased expression levels of Wnt antagonists DKK-1 and sclerostin in SpA leads to increased Wnt signaling and osteoblast function, resulting in new bone formation. Mechanical stress also promotes inflammation and new bone formation at entheses.