Deciphering the Role of Microtubule Posttranslational Modifications and Calcium/Calmodulin-Dependent Kinase 2 Delta and Gamma on Osteocyte Function
AdvisorStains, Joseph P.
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AbstractThe skeleton serves a number of functions within the body, some of which emphasize the exceptional adaptability and continuous dynamics of this organ. Two functions of particular interest are the interpretation and translation of mechanical stimuli into biological outputs, and the mediation of mineral homeostasis. In order to serve the body in these ways, bone needs to synthesize coordinated responses to multiple concomitant signals. Osteocytes, the great orchestrators of bone, are suited to do this through their vast network of cell processes and through secretion of various signaling proteins. Previously, we have demonstrated that microtubules within osteocytes tune responsiveness to mechanical load. We postulate that the accumulation of certain microtubule posttranslational modifications occurs broadly throughout the body with age and potentially contributes to the progression of osteopenia and sarcopenia. Here, I present data to support aging-dependent alterations in microtubule profile, and that individual tubulin posttranslational modifications are not sufficient to de-sensitize mechano-transduction in osteocytes alone. Since osteocytes are confined to the bone matrix, they secrete proteins to communicate with distant organ systems as well as with osteoblasts and osteoclasts locally on the surface of the bone. Regulation of these secretory factors within the osteocyte can ultimately impact bone formation and resorption. One such factor is fibroblast growth factor 23 (FGF23), a systemic regulator of phosphate concentration. When we hypothesized that deletion calcium/calmodulin-dependent kinase 2 (CaMKII), an essential component of an osteocyte mechano-transduction cascade we had already described, would diminish load-induced bone formation in vivo, we uncovered a basal increase in FGF23 and a dysfunction in mineral homeostasis. I describe here the profoundly osteopenic Ocn-cre:Camk2delta/Camk2gamma dCKO mice, with fragile bones containing enlarged osteoid seams, consistent with FGF23-induced hypophosphatemia. Bone-resident tissue non-specific alkaline phosphatase (TNAP) was reduced in these mice too, potentially adding to the under-mineralized phenotype. Disruption of late osteoblast/osteocyte physiology also blunted osteoblast activity and elevated osteoclast activity. We demonstrate an exciting new role for CaMKIId/g in bone, underpinning osteocyte-dependent regulation of bone mass, bone quality, and phosphate homeostasis. These data will provide the basis for future work uncovering the mechanism through which CaMKIId/gconducts each of these functions.
DescriptionUniversity of Maryland, Baltimore, School of Medicine, Ph.D., 2023
Calcium-Calmodulin-Dependent Protein Kinase Type 2