Regulation of Alveolar Bone Marrow MSC Senescence in Skeletal Aging and Periodontitis

ABSTRACT Aged craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects. Advanced age is a critical risk factor for many chronic and debilitating skeletal diseases including osteoporosis and periodontitis. Periodontitis is the inflammatory destruction of alveolar bone and periodontal connective tissue, resulting in the loss of tooth support. The disease susceptibility and severity increase dramatically with age, leading to a significant public health concern in the aging society. However, the mechanisms that drive craniofacial skeletal aging and age-related exacerbation of periodontitis remain largely unknown. Cellular senescence, the halting of proliferation for aged and damaged cells, play an important role in age- related chronic diseases including diabetes, osteoporosis and periodontitis. Mesenchymal stem cells (MSCs) possess self-renewal ability and multiple lineage potentials. Exhaustion of the MSC pool through senescence represents one of the hall marks for skeletal aging. Senescent MSCs lose potential for proliferation, self-renewal and osteogenic differentiation, contributing to the impaired bone mass and delayed repair in long-bone. MSC senescence is also associated with age-induced acculumation of oxidative stress, mitochondrial dysfunction and DNA damage. The stress-induced senescence could alter MSC-mediated immunomodulation through senescence-associated secretory phenotype (SASP). The direct evidence on the molecular link between MSC senescence and age-related craniofacial bone loss is lacking. Notably, alveolar bone marrow derived MSCs (aBMSCs), compared to long-bone MSCs, are more suitable for craniofacial repair, but exhibit niche-specific behaviors and responses to environmental stimuli. Peroxisome proliferator-activated receptor γ coactivators 1α (PGC-1α) is a transcriptional coactivator with essential roles in mitochondrial biogenesis and regulation of oxidative stress in various mitochondria-rich tissues. Recently, we found that PGC-1α directly regulates cell fate decisions of MSCs to protect against skeletal aging and osteoporosis. PGC-1α depletion also impaired ROS defense in MSCs, resulting in increased oxidative stress. However, the role of PGC-1α in MSC senescence and craniofacial skeletal tissue is unknown. Based on our preliminary experiments, MSC-specific depletion of PGC-1α significantly exacerbated age-induced trabecular bone loss in the mandible. Global depletion of PGC-1α exacerbated periodontal inflammation and bone loss in murine periodontitis models. Intriguingly, in vitro assays revealed that lack of PGC-1α promoted replicative senescence of aBMSCs. Thus, we hypothesize that PGC-1α modulates aBMSC senescence via regulation of oxidative stress to impact age-related craniofacial and periodontal bone loss. To test our hypothesis, we propose the following aims:1) To determine if PGC-1α regulates senescence of aBMSCs and craniofacial skeletal aging; 2) To determine if PGC-1α regulates cellular senescence to influence age-exacerbated periodontal bone loss; 3) To elucidate the underlying molecular mechanism of how PGC-1α modulates aBMSC senescence.