Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab

@article{Lacey2012BenchTB,
  title={Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab},
  author={David L. Lacey and William J. Boyle and William S. Simonet and Paul J. Kostenuik and William C. Dougall and John K Sullivan and Javier San Martin and Roger D. Dansey},
  journal={Nature Reviews Drug Discovery},
  year={2012},
  volume={11},
  pages={401-419}
}
Bone is a complex tissue that provides mechanical support for muscles and joints, protection for vital organs, a mineral reservoir that is essential for calcium homeostasis, and the environment and niches required for haematopoiesis. The regulation of bone mass in mammals is governed by a complex interplay between bone-forming cells termed osteoblasts and bone-resorbing cells termed osteoclasts, and is guided physiologically by a diverse set of hormones, cytokines and growth factors. The… 

Biology of the RANKL–RANK–OPG System in Immunity, Bone, and Beyond

The basic biology of the RANKL–RANK–OPG system is summarized, its cell-type specific functions to system-wide mechanisms of development and homeostasis are related, and emerging areas of interest for this cytokine group are highlighted.

RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives

Pre-clinical and clinical evidence is highlighted for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings and the exact role of OPG in breast tumorigenesis is still unclear.

Roles of the RANKL–RANK Axis in Immunity—Implications for Pathogenesis and Treatment of Bone Metastasis

The role of RANKL and RANK in the immune microenvironment and bone metastases is highlighted and data on the role of the regulatory mechanism of immunity in bone metastasing is reviewed, which could be verified through clinical efficacy of RankL inhibitors for cancer patients with bone metastasis.

Bone metabolism and the development of denosumab: a narrative review

Denosumab can specifically block RANKL, thereby inhibiting the activity of osteoclasts and blocking the development of disease, and has been approved by the U. S. Food and Drug Administration for osteoporosis, solid tumor bone metastasis, GCT of bone, malignant tumor hypercalcemia and other fields.

Receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin system in bone and other tissues (review).

Genetic studies have indicated that the RANKL/RANK/OPG system may be a key regulator in the formation of lymph nodes and in the autoimmune disease RA, which further suggests that the immune system may interact with the RankL/ RANK/ OPG system.

RANKL Cytokine: From Pioneer of the Osteoimmunology Era to Cure for a Rare Disease

An overview of the diverse roles of RANKL in the bone and immune systems is provided and the clinical features of RankL-deficient ARO patients and the results of preclinical studies are reviewed.

RANKL, a necessary chance for clinical application to osteoporosis and cancer-related bone diseases.

  • H. Yasuda
  • Biology, Medicine
    World journal of orthopedics
  • 2013
Anti-human RANKL monoclonal antibody has been successfully applied to the treatment of osteoporosis and cancer-related bone disorders in many countries and is a real example of applying basic science to clinical practice.

Role of RANKL/RANK in primary and secondary breast cancer.

Bone is one of the most preferential metastatic target sites of breast cancer. Bone possesses unique biological microenvironments in which various growth factors are stored and continuously released

CD39 Produced from Human GMSCs Regulates the Balance of Osteoclasts and Osteoblasts through the Wnt/β-Catenin Pathway in Osteoporosis

  • Wenbin WuZ. Xiao S. Zheng
  • Biology, Medicine
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2020
...

References

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Novel drugs specifically targeting RANK, RANKL, and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, periodontal disease, cancer metastases, and osteoporosis.

Do RANKL inhibitors (denosumab) affect inflammation and immunity?

The development of a human monoclonal antibody to RANKL, denosumab, constitutes a novel approach to prevent fragility fractures in osteoporosis, skeletal complications of malignancy, and potentially bone erosions in rheumatoid arthritis.

RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism.

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Data indicate that RANK is the intrinsic cell surface determinant that mediates osteoprotegerin ligand effects on bone resorption and remodeling as well as the physiological and pathological effects of calciotropic hormones and proresorptive cytokines.

Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease.

Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.

Structural and Functional Insights of RANKL–RANK Interaction and Signaling

The crystal structures of RANK and RANKL–RANK complex and the biological data presented in the paper are essential for not only understanding of the specific nature of the signaling mechanism and of disease-related mutations found in patients but also structure based drug design.

Increased RANKL/OPG mRNA Ratio in Iliac Bone Biopsies From Women with Hip Fractures

Actin normalized mRNA levels for OPG and interleukin (IL)-6 were significantly lower in fracture patients, with a significantly higher RANKL/OPG ratio in patients with fractures, and there was no significant difference in tumor necrosis factor (TNF), IL-1,IL-1ra, or IL-7 expression.

Continuous RANKL Inhibition in Osteoprotegerin Transgenic Mice and Rats Suppresses Bone Resorption without Impairing Lymphorganogenesis or Functional Immune Responses1

Prenatal RANKL inhibition did not impair lymph node development, nor did continuous life-long RankL inhibition cause obvious changes in innate or humoral immune responses in mice or rats.

Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis

Here, it is demonstrated for the first time that OPG-Fc treatment of mice with established bone metastases resulted in an overall improvement in survival and the essential role for RANKL in this process is supported.

RANK ligand is a prerequisite for cancer‐associated osteolytic lesions

P induces osteoclastic bone resorption through the transactivation of the RANKL gene on stromal/osteoblastic cells, affording a bone microenvironment conducive to the survival of PTHrP‐producing cancer cells.
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