RANK, RANKL and osteoprotegerin in bone biology and disease

Wright, Helen L.; McCarthy, Helen; Middleton, Jim; Marshall, Michael J.

doi:10.1007/s12178-009-9046-7

Cited by 172 publications

(135 citation statements)

References 67 publications

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“…Two of these isoforms are type II transmembrane glycoproteins that ensure cell-cell contact with osteoclasts and their precursors. The third isoform lacks transmembrane and intracellular domains and acts as soluble ligand (sRankl) allowing diffusion to activate target cells (Ikeda et al, 2001; reviewed by Wright et al, 2009). Mice overexpressing soluble or membrane bound forms of Rankl ubiquitously, die after E18.5 due to unknown reasons (Mizuno et al, 2002).…”

Section: Rankl Overexpression In Medaka Results In An Osteoporotic Phmentioning

confidence: 99%

Rankl-induced osteoclastogenesis leads to loss of mineralization in a medaka osteoporosis model

et al. 2012

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SUMMARYOsteoclasts are macrophage-related bone resorbing cells of hematopoietic origin. Factors that regulate osteoclastogenesis are of great interest for investigating the pathology and treatment of bone diseases such as osteoporosis. In mammals, receptor activator of NF-B ligand (Rankl) is a regulator of osteoclast formation and activation: its misexpression causes osteoclast stimulation and osteoporotic bone loss. Here, we report an osteoporotic phenotype that is induced by overexpression of Rankl in the medaka model. We generated transgenic medaka lines that express GFP under control of the cathepsin K promoter in osteoclasts starting at 12 days post-fertilization (dpf), or Rankl together with CFP under control of a bi-directional heat-shock promoter. Using long-term confocal time-lapse imaging of double and triple transgenic larvae, we monitored in vivo formation and activation of osteoclasts, as well as their interaction with osteoblasts. Upon Rankl induction, GFP-positive osteoclasts are first observed in the intervertebral regions and then quickly migrate to the surface of mineralized neural and haemal arches, as well as to the centra of the vertebral bodies. These osteoclasts are TRAP (tartrate-resistant acid phosphatase) and cathepsin K positive, mononuclear and highly mobile with dynamically extending protrusions. They are exclusively found in tight contact with mineralized matrix. Rankl-induced osteoclast formation resulted in severe degradation of the mineralized matrix in vertebral bodies and arches. In conclusion, our in vivo imaging approach confirms a conserved role of Rankl in osteoclastogenesis in teleost fish and provides new insight into the cellular interactions during bone resorption in an animal model that is useful for genetic and chemical screening.

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Section: Rankl Overexpression In Medaka Results In An Osteoporotic Phmentioning

confidence: 99%

Rankl-induced osteoclastogenesis leads to loss of mineralization in a medaka osteoporosis model

et al. 2012

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“…Accordingly, OPG has been shown to be an effective inhibitor of maturation and activation of osteoclasts in vitro and in vivo (5,6). The ratio between RANKL and OPG elegantly regulates the orientation of bone metabolism to either bone formation or resorption; therefore, dysregulation of this ratio causes an imbalance between bone formation and resorption and results in bone diseases such as osteoporosis, rheumatoid arthritis, and osteolytic bone metastasis (7)(8)(9)(10). For the same reasons, mutations in RANK, OPG, or RANKL are associated with genetic skeletal abnormalities such as autosomal recessive osteopetrosis (ARO) (11,12).…”

mentioning

confidence: 99%

Structure-based development of a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis

Nguyen

Jin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The receptor activator of nuclear factor-κB (RANK) and its ligand RANKL, which belong to the tumor necrosis factor (TNF) receptor-ligand family, mediate osteoclastogenesis. The crystal structure of the RANKL ectodomain (eRANKL) in complex with the RANK ectodomain (eRANK) combined with biochemical assays of RANK mutants indicated that three RANK loops (Loop1, Loop2, and Loop3) bind to the interface of a trimeric eRANKL. Loop3 is particularly notable in that it is structurally distinctive from other TNF-family receptors and forms extensive contacts with RANKL. The disulfide bond (C125-C127) at the tip of Loop3 is important for determining the unique topology of Loop3, and docking E126 close to RANKL, which was supported by the inability of C127A or E126A mutants of RANK to bind to RANKL. Inhibitory activity of RANK mutants, which contain loops of osteoprotegerin (OPG), a soluble decoy receptor to RANKL, confirmed that OPG shares the similar binding mode with RANK and OPG. Loop3 plays a key role in RANKL binding. Peptide inhibitors designed to mimic Loop3 blocked the RANKL-induced differentiation of osteoclast precursors, suggesting that they could be developed as therapeutic agents for the treatment of osteoporosis and bone-related diseases. Furthermore, some of the RANK mutations associated with autosomal recessive osteopetrosis (ARO) resulted in reduced RANKL-binding activity and failure to induce osteoclastogenesis. These results, together with structural interpretation of eRANK-eRANKL interaction, provided molecular understanding for pathogenesis of ARO.

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“…In our study, TRAP was highly expressed in terminally differentiated RAW264.7 cells. OPG reduces the RANK mRNA levels in osteoclasts (Fu et al 2013a) and RANK is highly expressed in osteoclast precursors at the mRNA level (Wright et al 2009). However, directly contradicting these findings, our experiments revealed little expression of RANK in preosteoclasts and an OPG-induced enhancement of this expression.…”

Section: Discussionmentioning

confidence: 99%

Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function

Zhao

Dai

et al. 2015

Cytotechnology

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This study aimed to investigate the effects of osteoprotegerin (OPG), a decoy receptor for receptor activator for nuclear factor jB ligand (RANKL), during the various stages of osteoclast differentiation, and additionally investigate its effects on osteoclast adhesion and activity. RAW264.7 murine monocytic cells were incubated with macrophage colony-stimulating factor and RANKL for 1, 3, 5, or 7 days, followed by an additional 24-h incubation in the presence or absence of OPG (80 ng/mL). We examined osteoclast differentiation and adhesion capacity using the tartrate-resistant acid phosphatase (TRAP) assay and immunofluorescence microscopy, and additionally examined cell growth in real time using the xCELLigence system. Furthermore, the expression levels of TRAP, RANK, integrin b3, matrix metalloproteinase 9, cathepsin K, carbonic anhydrase II, and vesicular-type H ? -ATPase A1 were examined using western blotting. OPG exposure on day 1 enhanced the osteoclast growth curve as well as adhesion, and increased RANK and integrin b3 expression. In contrast, exposure to OPG at later time points (days 3-7) inhibited osteoclast differentiation, adhesion structure formation, and protease expression. In conclusion, the biological effects of OPG exposure at the various stages of osteoclast differentiation were varied, and included the enhanced adhesion and survival of preosteoclasts, the block of differentiation from the early to the terminal stages of osteoclastogenesis, and suppression of mature osteoclast activation following OPG exposure during the terminal differentiation stage, suggesting that the effects of OPG exposure differ based on the stage of differentiation.

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RANK, RANKL and osteoprotegerin in bone biology and disease

Cited by 172 publications

References 67 publications

Rankl-induced osteoclastogenesis leads to loss of mineralization in a medaka osteoporosis model

Rankl-induced osteoclastogenesis leads to loss of mineralization in a medaka osteoporosis model

Structure-based development of a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis

Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function

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