Kalirin and Osteocyte Dysfunction: Implications Across Skeletal Sites and Experimental Periodontitis

SUMMARY/ABSTRACT The goal of this study is to elucidate how Kalirin, a multifunctional GTP/GDP exchange factor, regulates osteocyte function and bone mass across various skeletal sites, with a particular focus on periodontal bone. Osteocytes, the most abundant bone cell type, play a key role in bone remodeling, yet the specific mechanisms governing their function remain unknown. Mice with global Kalirin deletion (Kal-KO) display low bone mineral density, attributed in part to dysfunctional osteocytes as shown by decreases in osteocyte morphology and dendrite length, altered expression of osteocyte genes and an increase in osteocyte apoptosis in cortical and trabecular bone. We found dental, craniofacial and alveolar deficiencies in global Kal-KO mice. Given that osteocyte viability is linked with the pathology of periodontitis, we hypothesize that osteocyte specific deletion of Kalirin will decrease bone mineral density across different skeletal sites and exacerbate bone loss in a mouse model of experimental periodontitis. Using osteocyte-targeted Kalirin knockout mice (Kal-Dmp1Cre), we will examine changes in bone mass and architecture as well as osteocyte morphology, viability, and function across different skeletal sites, and in experimental periodontitis induced by ligation of maxillary molars. In Specific Aim 1, we will characterize the effects of osteocyte-targeted Kalirin deletion on bone mass and architecture at craniofacial, periodontal, spine, and femoral sites using µCT, histology, and histomorphometric analysis. Changes in osteocyte morphology and function will be investigated through histological staining of tissue and analysis of primary osteocyte morphology and gene expression in vitro. In Specific Aim 2, we will investigate if Kalirin deficiency in osteocytes exacerbates periodontal bone loss during experimental periodontitis. We will perform a ligature-induced bone loss study in osteocyte-targeted Kalirin deletion (Kal-Dmp1Cre) compared to control (Kal- FF) mice. Bone changes will be analyzed by µCT, histology, and histomorphometric methods. In addition, in situ changes in the expression of osteocytic genes and inflammatory cytokines in LIP maxillae and control maxillae from these mice will be performed by RNAscope and complemented with analysis of gingival crevicular fluid. Both male and female mice will be used for all studies. These studies aim to enhance the overall understanding of Kalirin’s role in osteocyte function and bone health at different skeletal sites, potentially leading to new therapeutic targets for preventing bone loss and improving patient care, particularly in the context of periodontitis and other bone loss diseases. The mentorship, training, resources and facilities available to me during my journey towards my DDS/PhD will ensure a positive trajectory towards my future career as an independent dental clinician scientist.