Bone is a dynamic organ that is continually being broken down and reconstructed. Remodeling is achieved through the synergized efforts of osteoclasts, which are tissue-specific macrophages that digest bone matrix, and osteoblasts, which synthesize and deposit new matrix. Osteoclast activity and osteoblast activity are tightly coupled to maintain bone homeostasis. Dysregulation of this balance, which often occurs during aging or sex-hormone deprivation, underlies a number of bone-related pathologies including osteoporosis, osteopetrosis, Paget’s disease, and bone metastases. While treatments exist, they often target the symptoms and not the underlying disease. As a result, there is a great need to return to the basic biology of bone cells to extend our understanding of their function and regulation to ultimately improve therapy options.
CD82 is a widely expressed member of the tetraspanin family of proteins that are known to control cell signaling, adhesion, fusion, and migration. CD82 is upregulated 9.4-fold during osteoclast differentiation in vitro, but its specific function in osteoclasts and in bone homeostasis in all is unknown. We used our mouse model of global CD82 deletion to reveal that CD82deficient bones are smaller in diameter and weaker, but display no change in bone density due to simultaneous defect in both osteoclasts and osteoblasts. Unexpectedly, CD82 loss also enhanced bone marrow adipogenesis. To better address the role of CD82 in osteoclasts, we utilized a model of myeloid-specific loss of CD82, which results in greater bone volume despite an increase in osteoclast number and size. This is accompanied by functional defects and compromised signaling to integrin ?v?3, SRC, SYK, and VAV. We also discovered that expression of CLEC2 and its ligand, podoplanin, molecules that also signal to SYK and VAV, are increased during osteoclastogenesis and are negatively regulated by CD82.
|Commitee:||Davis, Julie, McHugh, Kevin, Yang, Tao|
|School:||Van Andel Research Institute|
|School Location:||United States -- Michigan|
|Source:||DAI-B 79/11(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology, Cellular biology|
|Keywords:||Bone, CD82, Homeostasis, Tetraspanin|
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