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Matrix-embedded cells control osteoclast formation.


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.

Pubmed ID: 21909103


  • Xiong J
  • Onal M
  • Jilka RL
  • Weinstein RS
  • Manolagas SC
  • O'Brien CA


Nature medicine

Publication Data

October 12, 2011

Associated Grants

  • Agency: NCRR NIH HHS, Id: 1UL1RR029884
  • Agency: NIA NIH HHS, Id: AG13918
  • Agency: NIAMS NIH HHS, Id: AR049794
  • Agency: BLRD VA, Id: I01 BX000294
  • Agency: NIAMS NIH HHS, Id: R01 AR049794
  • Agency: NIAMS NIH HHS, Id: R01 AR049794-09

Mesh Terms

  • Analysis of Variance
  • Animals
  • Bone Matrix
  • Bone Remodeling
  • Bone Resorption
  • Bone and Bones
  • Chondrocytes
  • Histological Techniques
  • Mice
  • Mice, Transgenic
  • Osteoblasts
  • Osteoclasts
  • Polymerase Chain Reaction
  • RANK Ligand