The Role of cyclooxygenase-2 and parathyroid hormone in mesenchymal progenitor cell function during scenescent fracture repair

Thesis (Ph. D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology and Laboratory Medicine, 2008.For over thirty years it has been well established in the clinical setting that the rate and quality of fracture healing declines with age. This results in prolonged pain, increased risk of mortality and morbidity, and many times permanent disability. The literature suggests that aging results in discrete morphological and molecular changes which include delays in chondrogenesis and endochondral ossification, two vital processes in bone repair. Little progress, however, has been made to comprehensively define mechanisms underlying these differences and to develop new therapeutic strategies to improve fracture repair in humans and animal models. The current thesis confirms that aged mouse fractures have a decreased rate of healing associated with delayed chondrogenesis and chondrocyte maturation, decreased fracture callus mineralization and vascularization, and dysregulation of genes anabolic to fracture repair such as Cyclooxygenase-2 (COX-2) and Bone Morphogenetic Protein-2 (BMP-2). COX-2 is the rate limiting enzyme involved in prostaglandinE2 (PGE2) synthesis and is a critically important enzyme for bone repair. Senescent regulation of these critical genes leads to perturbation in temporally distal events such as chondrogenesis, bone formation, and remodeling. Adjuvant therapy with an EP4 selective agonist rescues inefficiencies in chondrogenesis and reduced bone formation observed in aging. Furthermore, intervention with Parathyroid Hormone (PTH) increased chondrogenesis and bone formation in fractured aged mice to levels exceeding those observed in young controls. PTH therapy likely induces Indian Hedgehog (Ihh) release from pre-hypertrophic chondrocytes enhancing chondrocyte proliferation and osteoblast development through modulation of Runx2. Overall this thesis examines the role of periosteal progenitor cells and their function in bone repair in the context of aging. The systemic and microenvironment of the aged animal provides less than optimal inflammatory and hormonal stimuli to promote the proliferation and differentiation of precursors into the cellular components of fracture repair. When given sufficient stimulus, aged mice demonstrate healing parameters similar to young animals. This thesis, essentially, provides the framework for future investigation into mesenchymal stem cells and their role in senescent fracture healing