Matrix-embedded cells control osteoclast formation

By J. Xiong, M. Onal, R. Jilka, R. Weinstein, S. Manolagas, Charles A. O’Brien. Nature Medicine, 2011

1,279 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/385dcf04844646bfb33550a03f01315212e0a8cc

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Citations in the corpus

Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. (2014, background): “Recent in vivo studies in genetically manipulated mice demonstrated osteopetrosis in those mice lacking RANKL throughout the osteoblast lineage, and less markedly so in mice with deletion in mature cells and osteocytes only.(36,37) These data suggested that it is not only early osteoblast precursors”
Estrogen and the Skeleton (2012, positive): “Moreover, given the recent evidence noted above for the osteocyte being an important source of RANKL in bone (12, 13), it is possible that osteocyte apoptosis results in an increase in RANKL in the bone microenvironment, perhaps due to RANKL release from the apoptotic osteocytes or via effects of th”
Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation (2017, background): “…nuclear factorκB ligand (RANKL; encoded by Tnfsf11), which are expressed by osteoblast-lineage cells (Fumoto et al., 2014) or osteocytes (Nakashima et al., 2011; Xiong et al., 2011), are required for the differentiation of osteoclast precursors into mature osteoclasts (Teitelbaum and Ross, 2003).”
Development of the endochondral skeleton. (2013, background): “…cartilage leads to further degradation of the mineralized matrix by MMP9 produced by a resorptive cell type (the so-called chondroclast) (Vu et al. 1998), whose formation may be stimulated by RANKL (receptor activator of NF-kB ligand) produced by hypertrophic chondrocytes (Xiong et al. 2011).”
Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015, background): “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].”