Minireview: The OPG/RANKL/RANK System

Khosla, Sundeep

doi:10.1210/endo.142.12.8536

Cited by 1,515Bone Metabolism and DiseasesBone health and osteoporosis researchRheumatoid Arthritis Research and Therapies

Minireview: The OPG/RANKL/RANK System

Khosla, Sundeep·2001·Endocrinology

DOI 10.1210/endo.142.12.8536

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Abstract

The identification of the OPG/RANKL/RANK system as the dominant, final mediator of osteoclastogenesis represents a major advance in bone biology. It ended a long-standing search for the specific factor produced by preosteoblastic/stromal cells that was both necessary and sufficient for osteoclast development. The initial cloning and characterization of OPG as a soluble, decoy receptor belonging to the TNF receptor superfamily was the first step that eventually led to an unraveling of this system. Soon thereafter, the molecule blocked by OPG, initially called OPG-ligand/osteoclast differentiating factor (ODF) and subsequently RANKL, was identified as the key mediator of osteoclastogenesis in both a membrane-bound form expressed on preosteoblastic/stromal cells as well as a soluble form. RANKL, in turn, was shown to bind its receptor, RANK, on osteoclast lineage cells. The decisive role played by these factors in regulating bone metabolism was demonstrated by the findings of extremes of skeletal phenotypes (osteoporosis vs. osteopetrosis) in mice with altered expression of these molecules. Over the past several years, work has focused on identifying the factors regulating this system, the signaling mechanisms involved in the RANKL/RANK pathway, and finally, potential alterations in this system in metabolic bone disorders, from the extremely common (i.e. postmenopausal osteoporosis) to the rare (i.e. familial expansile osteolysis).

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The balance between OPG and RANKL levels is a central determinant of osteoclast activation and bone resorption.
“Thus, the ratio between the levels of OPG and RANKL is a key factor in the control of osteoclast activation and bone resorption (120).”
From The Activity of Peptides of the Calcitonin Family in Bone (2019) · cites this paper as [120]
OPG acts as a decoy receptor for osteoclast activating factor and a receptor activator of RANKL and impairs osteoclast function.
“OPG acts as a decoy receptor for osteoclast activating factor and a receptor activator of RANKL and impairs osteoclast function [158].”
From Emerging role of liver-bone axis in osteoporosis (2024) · cites this paper as [158]

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Authors: Khosla, S.
Affiliations: Mayo Clinic (US)
Corresponding author: Khosla, Sundeep
ORCID: Khosla, Sundeep
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2001-12
Volume: 142
Issue: 12
Pages: 5050-5055
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/endo.142.12.8536
OpenAlex: W2168451480
Semantic Scholar: eedbd21edfd4c221424281c1f92426223aaac5db
Cited by: 1,515
References: 59
Citations by year: 2026: 20 · 2025: 37 · 2024: 36 · 2023: 27 · 2022: 46 · 2021: 49 · 2020: 53 · 2019: 67 · 2018: 79 · 2017: 72 · 2016: 70 · 2015: 78 · 2014: 80 · 2013: 97 · 2012: 81
FWCI: 14.93
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Public Health Service
National Institute on Aging (AG 04875, P01AG004875)
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: osteoclastogenesis, RANKL, RANK, osteoprotegerin, TNF receptor superfamily, bone metabolism, osteoporosis, osteopetrosis, postmenopausal osteoporosis, RANK/RANKL signaling, metabolic bone disease
MeSH terms: Animals, Bone Diseases, Metabolic, Carrier Proteins, Cell Division, Glycoproteins, Humans, Membrane Glycoproteins, Osteoclasts, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B

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