BoneKEy Reports | BoneKEy Watch
Osteoclastic bone resorption depends on talin 1 and its receptor Rap1
DOI:10.1038/bonekey.2013.62
Inside-out activation of integrins via intracellular signaling plays a central role in the process of bone resorption carried out by osteoclasts attached to the surface of bone. This activation involves interaction between the β-integrin cytoplasmic domain and talin 1 (TLN1), a cytosol-based adaptor protein that connects β-integrins with the actin cytoskeleton.
In this study, Zou et al. generated two strains of mice, one with a specific TLN1 knockout in all cells with their entire osteoclast lineage and another with a deletion of the TLN1 gene in mature osteoclasts only. This revealed that osteoclasts deficient in talin were unable to resorb bone as efficiently; mice unable to express TLN1 in mature osteoclasts showed enhanced trabecular volume, with a 5 × increase in bone mass, despite having normal numbers of osteoclasts. These mice were effectively protected from osteoporosis induced by ovariectomy. Osteoclast precursor cells deficient in talin were unable to develop into mature osteoclasts, but the resulting effects on bone mass were less marked.
Studies also showed that osteoclasts that lacked Rap1 were similarly dysfunctional, and mice with Rap1-deficient osteoclasts showed a significant increase in bone mass.
Editor’s comment: The authors demonstrate the role of inside-out signaling from c-Fms via Rap1 to promote talin association and activation of integrins. Because the Rap1–talin signal can activate not only β3-integrin but also other β-integrins, inhibition of this signaling in mature osteoclasts can be an effective therapeutic approach for inhibiting enhanced osteoclastic bone resorption.
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