Low kindlin-3 levels in osteoclasts of kindlin-3 hypomorphic mice result in osteopetrosis due to leaky sealing zones

ABSTRACT: Osteoclasts form special integrin-mediated adhesion structures called sealing zones that enable them to adhere to and resorb bone. Sealing zones consist mainly of densely packed podosomes tightly inter-connected by actin fibers. Their formation requires the presence of the hematopoietic integrin regulator kindlin-3. In the current study, we investigated osteoclasts and their adhesion structures in kindlin-3 hypomorphic mice expressing only 5-10% of kindlin-3. Low kindlin-3 expression reduces integrin activity, results in impaired osteoclast adhesion and signaling, and delays cell spreading. Despite these defects, in vitro generated kindlin-3-hypomorphic osteoclasts arrange their podosomes into adhesion patches and belts, which show abnormal podosome and actin organization. Remarkably, kindlin-3-hypomorphic osteoclasts form sealing zones when cultured on calcified matrix in vitro and on bone surface in vivo. However, functional assays as well as immunohistochemical staining and electron micrographs of bone sections showed that they fail to properly seal the resorption lacunae, which is required for secreted proteases to be able to digest bone matrix. This results in mild osteopetrosis. Our study reveals a new, hitherto understudied function of kindlin-3 as an essential organizer of integrin-mediated adhesion structures, such as sealing zones.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Platelet, Neutrophil, Bone Marrow, Fibroblast, Macrophage

SUBMITTER: Theresa Bock  

LAB HEAD: Markus Moser

PROVIDER: PXD026711 | Pride | 2021-11-25

REPOSITORIES: Pride