Matrix-embedded cells control osteoclast formation
Open accessAbstract
Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and thought to be supplied by osteoblasts or their precursors, thereby linking bone formation to resorption. However, RANKL is expressed by a variety of cell types, and it is unclear which of them are essential sources for osteoclast formation. Here we have used a mouse strain in which RANKL can be conditionally deleted and a series of Cre-deleter strains to demonstrate that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to adult bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.
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In the initiation phase, under RANKL and M-CSF, hematopoietic stem cells are recruited to specific bone surface areas and differentiate into mature osteoclasts that initiate bone resorption.
“In the initiation phase, under the action of osteoclastogenic factors including RANKL and M-CSF, hematopoietic stem cells are recruited to specific bone surface areas and differentiate into mature osteoclasts that initiate bone resorption [167, 168].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [168]
Osteocytes act as the main source of RANKL to promote osteoclastogenesis.
“There is evidence that osteocytes act as the main source of RANKL to promote osteoclastogenesis [167, 168], although this factor has also been demonstrated to be produced by other cell types such as stromal cells [194], osteoblasts, and fibroblasts [88, 89].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [168]
Osteoclast fusion requires RANKL, which is highly expressed by BLCs, osteoblasts in the growing skeleton, and osteocyte arborizations that reach the bone surface in adults.
“Fusion also requires RANKL, which is highly expressed by BLCs;161 osteoblasts in the growing skeleton; and osteocyte arborizations that reach the bone surface in adults.51,52”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [52]
In mice, osteocytes are probably the most relevant source of RANKL during estrogen deficiency.
“In the mouse, osteocytes are probably the most relevant source of RANKL in estrogen-deficient mice (29).”
From Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics (2016) · cites this paper as [29]
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- Authors
- Xiong, J., Onal, M., Jilka, R. L., Weinstein, R. S., Manolagas, S. C., & O'Brien, C. A.
- Affiliations
- University of Arkansas Medical Center (US)
- Venue
- Nature Medicine
- Published
- 2011-09-11
- Volume
- 17
- Issue
- 10
- Pages
- 1235-1241
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3192296
- OpenAlex
- W2087665466
- Cited by
- 1,304
- References
- 49
- Citations by year
- 2026: 51 · 2025: 52 · 2024: 57 · 2023: 70 · 2022: 74 · 2021: 85 · 2020: 103 · 2019: 105 · 2018: 80 · 2017: 91 · 2016: 75 · 2015: 111 · 2014: 101 · 2013: 126 · 2012: 105
- FWCI
- 45.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000294)
- National Institute on Aging (AG13918, P01AG013918)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR049794, R01AR049794)
- National Center for Research Resources (UL1RR029884)
- 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 › Bone and Dental Protein Studies
- Keywords
- RANKL, osteoclastogenesis, osteocytes, hypertrophic chondrocytes, bone remodeling, bone resorption, osteoblasts, osteoporosis, mechanical unloading, bone loss
- MeSH terms
- Analysis of Variance, Animals, Bone and Bones, Bone Matrix, Bone Resorption, Histological Techniques, Mice, Transgenic, Osteoblasts, Osteoclasts, Radiography, Polymerase Chain Reaction, Bone Remodeling, Chondrocytes, Mice, RANK Ligand
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