CAV-1 regulates osteocyte communication with osteoclast and osteoblast precursors

Mechanical forces regulate bone homeostasis through complex mechanisms involving diverse mechanoreceptors in osteocytes. PTH/PTHrP receptor type I (PTH1R) regulates the communication with osteoclast precursors by translocating to the primary cilia in osteocytes. Caveolin-1 (CAV-1), the main structural component of caveolae, has also been proposed as an osteocyte mechanosensor, and was recently found at the base of primary cilia in epithelial cells. We hypothesize that CAV-1, PTH1R and the primary cilia collaborate to regulate osteocyte communication with other cells in the bone microenvironment in response to mechanical stimuli. Conditioned media (CM) obtained from mechanically (FF)- or PTH1R(PTHrP)-stimulated MLO-Y4 osteocytes inhibited the migration of preosteoclastic cells and osteoclast differentiation while stimulated mesenchymal progenitor cell (MSC) migration; these actions were inhibited by Cav-1 silencing of osteocytes. Evaluation of a previously published proteomic analysis of the osteocytic secretome showed decreased CXCL5 and increased osteopontin secretion by mechanically-stimulated osteocytes. Specific antibody neutralization revealed that CXCL5 and osteopontin have a pivotal role on preosteoclast migration and differentiation and MSC migration, respectively. Cav-1 silencing decreased the length and percentage of primary cilia harboring PTH1R in osteocytes. We propose a collaboration between primary cilia and CAV-1 which controls osteocyte communication with osteoclast and osteoblast precursors through the secretion of CXCL5 and osteopontin.