A NOVEL ROLE OF THE MECHANO-SENSING PROTEIN P130CAS IN SUPPORTING BONE HOMEOSTASIS

Abstract

A VARIETY OF BIOLOGICAL EVENTS, INCLUDING INFLAMMATORY RESPONSES, ARE SUBJECT TO MECHANICAL INFLUENCE. HOWEVER, IT REMAINS LARGELY ELUSIVE HOW INFLAMMATION-RELATED SIGNALING IS MECHANICALLY MODULATED. HERE WE SHOW THAT P130CAS (CRK-ASSOCIATED SUBSTRATE, HEREAFTER REFERRED TO AS CAS), WHICH HAS PREVIOUSLY BEEN REPORTED TO ACT AS A CELLULAR MECHANO-SENSOR, PARTICIPATES IN INFLAMMATORY SIGNALING. UPON TREATMENT WITH THE INFLAMMATORY CYTOKINE TNF-A, CAS TRANSLOCATES INTO THE NUCLEUS AND INTERFERES WITH THE PHYSICAL ASSOCIATION BETWEEN THE ACETYLTRANSFERASE P300 AND NF-KB. WE FURTHER TEST IF THE MECHANOSENSING MOLECULE CAS PLAYS A ROLE IN THE RESPONSE OF OSTEOCYTES TO SHEAR FLOW. OSTEOCYTE-SPECIFIC CAS KNOCKOUT MICE EXHIBIT AN OSTEOPENIA ASSOCIATED WITH AN INCREASED OSTEOCLASTIC BONE RESORPTION BASED ON AN ENHANCED RANKL EXPRESSION DEPENDING ON NF-KB. THE RESULTS SHOW THAT THE CAS-NF-KB AXIS SUPPORTS THE NORMAL BONE METABOLISM, PROVIDING NOVEL INSIGHTS INTO THERAPEUTIC STRATEGIES FOR ATRO