Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82
Alexis Bergsma,
Sourik S. Ganguly,
Mollie E. Wiegand,
Daniel Dick,
Bart O. Williams,
Cindy K. Miranti
Affiliations
Alexis Bergsma
Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI, USA
Sourik S. Ganguly
Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI, USA; Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
Mollie E. Wiegand
Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
Daniel Dick
Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI, USA
Bart O. Williams
Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI, USA
Cindy K. Miranti
Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, MI, USA; Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Corresponding author at: University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA.
We used a myeloid-specific Cre to conditionally delete CD82 in mouse osteoclasts and their precursors. In contrast to global loss of CD82 (gKO), conditional loss of CD82 (cKO) in osteoclasts does not affect cortical bone, osteoblasts, or adipocytes. CD82 loss results in greater trabecular volume and trabecular number but reduced trabecular space in 6-month old male mice. Though this trend is present in females it did not reach significance; whereas there was an increase in osteoclast numbers and eroded surface area only in female cKO mice. In vitro, there is an increase in osteoclast fusion and defects in actin assembly in both gKO and cKO mice, irrespective of sex. This is accompanied by altered osteoclast morphology and decreased release of CTX in vitro. Integrin αvβ3 expression is reduced, while integrin β1 is increased. Signaling to Src, Syk, and Vav are also compromised. We further discovered that expression of Clec2 and its ligand, Podoplanin, molecules that also signal to Syk and Vav, are increased in differentiated osteoclasts. Loss of CD82 reduces their expression. Thus, CD82 is required for correct assembly of the cytoskeleton and to limit osteoclast fusion, both needed for normal osteoclast function. Keywords: Tetraspanin, Osteoclast, Adhesion, Cytoskeleton, Genetic mouse model