RANKL Stimulates Inducible Nitric-oxide Synthase Expression and Nitric Oxide Production in Developing Osteoclasts

Abstract

Normal bone remodeling requires a homeostatic balance between the activities of bone-forming osteoblasts and bone-resorbing osteoclasts (OCs).3 Excessive OC bone resorption leads to bone loss in many skeletal pathologies such as rheumatoid arthritis, periodontal disease, postmenopausal osteoporosis, implant osteolysis, and tumor-associated bone loss (1). OCs develop from hematopoietic precursors that fuse and differentiate into multinucleated bone-resorbing OCs in response to the essential tumor necrosis factor (TNF) family-related signal molecule receptor activator of NF-B (RANK) ligand (RANKL) in the presence of permissive levels of macrophage colony-stimulating factor (M-CSF) (2, 3). RANKL expressed on the surface of osteoblasts, bone marrow stromal cells, or vascular endothelial cells or secreted by activated T cells directly engages a membrane receptor, RANK, on OC precursors and mature OCs to trigger multiple intracellular signaling cascades that stimulate OC gene expression, development, function, and survival (2, 3). RANKL/RANK interactions are specifically blocked by osteoprotegerin (OPG), a soluble decoy receptor released by osteoblast, stromal, vascular endothelial, and other cells that binds RANKL to inhibit OC formation and bone resorption in vivo and in vitro (2-4). The RANKL/OPG ratio critically determines net effects on OC formation and bone resorption, and increases in this ratio due to various inflammatory or proresorptive stimuli have been shown to significantly contribute to pathological bone loss in multiple skeletal disorders. Interestingly, although clearly essential for promoting OC formation and activity, RANKL was found recently to also trigger an autocrine negative feedback pathway in OC precursors that ultimately limits the extent of osteoclastogenesis concurrently stimulated by RANKL (5,6). This negative feedback pathway involves RANKL induction of interferon (IFN)-␤ in a c-Fos-dependent manner, followed by IFN-␤ inhibition of RANKL-induced c-Fos expression necessary for OC formation (5). OC formation and bone resorption are also inhibited by elevated levels of the multifunctional signal molecule nitric oxide (NO) in vivo and in vitro (7)(8)(9)(10)(11)(12)(13). NO is produced from L-arginine in an oxidative reaction catalyzed by NO synthase isoenzymes that are either constitutively expressed and calcium-activated (endothelial and neuronal NO synthase isoforms) or transcriptionally induced (inducible NO synthase (iNOS) isoform) in response to inflammatory stimuli (14). Previously, our group (8,12,15) and others (9, 16) have shown that OCs and related OC-like cells (as well as other bone cells) express iNOS and release NO

Orthodontic treatment effects on inflammatory marker profiles in saliva before and after 2 archwire changes

“…Excessive amounts of NO may contribute to tissue destruction in periodontitis [32] and increased NO reflected more-severe inflammation [29]. This could be partly due to NO restraining influence to osteoclastogenesis [33]. In the present study, we observed the trend of NO to decrease over periods of archwire changes.…”

Therapy discrimination via global sensitivity analysis of force-induced bone growth and adaptation

“…Consistent with proposed hypotheses [10], [12], [20] and experimental observations [13], [19], [21]- [25], the mathematical model employed here, presented in [1], links the mechanical loading with the bone remodeling process through the mechanotransduction activity of osteocytes. See Fig.…”

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

“…Nitrates may also affect osteoclasts and osteoblasts; NO may influence osteoclast activity, in part, via the receptor activator of NF‐kappaB ligand (RANKL)/osteoprotegerin (OPG) pathway. High levels of NO stimulate OPG, which binds to RANKL and prevents the binding of RANKL to the receptor activator of NF‐kappaB (RANK), decreasing osteoclast activity 48. eNOS global knockout animals exhibit lower BMD, bone formation, and osteoblast activity; with little to no effect on bone resorption, suggesting NO may be important for osteoblast function 49, 50.…”