The Role of Receptor Activator of Nuclear Factor-κB (RANK)/RANK Ligand/Osteoprotegerin: Clinical Implications
Abstract
CONTEXT: Receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK), and osteoprotegerin (OPG) play a central role in bone remodeling and disorders of mineral metabolism. EVIDENCE ACQUISITION: A PubMed search was conducted from January 1992 until 2007 for basic, observational, and clinical studies in subjects with disorders related to imbalances in the RANK/RANKL/OPG system. EVIDENCE SYNTHESIS: RANK, RANKL, and OPG are members of the TNF receptor superfamily. The pathways involving them in conjunction with various cytokines and calciotropic hormones play a pivotal role in bone remodeling. Several studies involving mutations in the genes encoding RANK and OPG concluded in the discovery of a number of inherited skeletal disorders. In addition, basic and clinical studies established a consistent relationship between the RANK/RANKL/OPG pathway and skeletal lesions related to disorders of mineral metabolism. These studies were a stepping stone in further defining the role of the RANK/RANKL/OPG pathway in osteoporosis, rheumatoid arthritis, bone loss associated with malignancy-related skeletal diseases, and its relationship to vascular calcifications. Subsequently, the further understanding of this pathway led to the development of new therapeutic modalities including the human monoclonal antibody to RANKL and recombinant OPG as a target for treatment of postmenopausal osteoporosis and multiple myeloma. CONCLUSIONS: The RANK/RANKL/OPG system mediates the effects of calciotropic hormones and, consequently, alterations in their ratio are key in the development of several clinical conditions. New agents with the potential to block effects of RANKL have emerged for treatment of postmenopausal osteoporosis and malignancy-related skeletal disease.
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The RANKL-RANK-OPG pathway is an essential regulatory pathway for bone metabolism, and its importance lies in its interaction with most of the pathophysiologic mechanisms by which smoking influences bone mass.
“A RANKL-RANK-OPG pathway is an essential regulatory pathway for bone metabolism and its importance lies in its interaction with most of the pathophysiologic mechanisms by which smoking influences bone mass.”
From The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms (2018) · cites this paper as [45]
The introduction (p. 1) calls the RANK/RANKL/OPG system a key mediator of bone remodeling, and “Regulatory Mechanisms of Bone Remodeling” (p. 1) describes its role in osteoclast formation and bone resorption. The copy does not connect the pathway to smoking or say that it interacts with most mechanisms by which smoking influences bone mass; searches for smoking, cigarettes, tobacco, and nicotine did not locate such a discussion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe activities of osteoblasts and osteoclasts are regulated by several factors, including the RANKL-RANK-OPG pathway, estradiol, various cytokines, and calciotropic hormones.
“The activities of both are regulated by several factors, including the RANKL-RANK-OPG pathway, estradiol, various cytokines, and calciotropic hormones [16, 45, 69].”
From The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms (2018) · cites this paper as [45]
The Regulatory Mechanisms of Bone Remodeling section (p. 1) says osteoclast activity is regulated by cytokines and calciotropic hormones, and that RANKL, RANK, and OPG govern osteoclast formation and activation. The Postmenopausal osteoporosis section (p. 2) reports an estradiol response in osteoblastic cells, but the paper does not establish that all the listed factors regulate the activities of both osteoblasts and osteoclasts. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEstrogen acts via suppression of bone resorption.
“Estrogen acts via suppression of bone resorption [43–45]”
From The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms (2018) · cites this paper as [45]
The RANKL-RANK-OPG pathway has great influence on osteoclast formation and activities.
“The RANKL-RANK-OPG pathway has great influence on osteoclast formation and activities [45, 91].”
From The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms (2018) · cites this paper as [45]
The RANKL-RANK-OPG pathway interacts with other factors influencing bone turnover, such as prostaglandin E2 and interleukins.
“This pathway interacts with other factors influencing bone turnover, such as prostaglandin E2 and interleukins [45, 69].”
From The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms (2018) · cites this paper as [45]
The RANKL-RANK-OPG pathway plays a key role in the processes by which smoking alters bone health.
“Among these, the RANKL-RANK-OPG pathway seems to play a key role in the processes by which smoking can alter bone health, as it is known to have a great influence on osteoclastogenesis and osteoclast function, as well as its interaction with most of the indirect pathophysiological mechanisms that influence bone turnover and bone mass [76,77].”
From Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic (2021) · cites this paper as [76]
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References 99 · Cited by 246
- Authors
- Vega, D., Maalouf, N. M., & Sakhaee, K.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Sakhaee, Khashayar
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2007-12-01
- Volume
- 92
- Issue
- 12
- Pages
- 4514-4521
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2045540294
- Cited by
- 246
- References
- 99
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 3 · 2023: 11 · 2022: 7 · 2021: 11 · 2020: 4 · 2019: 10 · 2018: 13 · 2017: 10 · 2016: 18 · 2015: 19 · 2014: 22 · 2013: 15 · 2012: 23
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- RANK/RANKL/OPG system, osteoprotegerin, RANK, RANKL, bone remodeling, mineral metabolism disorders, osteoporosis, postmenopausal osteoporosis, rheumatoid arthritis, multiple myeloma, bone loss, vascular calcification, calciotropic hormones, TNF receptor superfamily
- MeSH terms
- Animals, Bone Diseases, Humans, Biomarkers, Tumor, Bone Remodeling, Receptors, Tumor Necrosis Factor, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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