Osteoprotegerin in Bone Metabolism

Sammanfattning: Bone turnover, remodeling, is a constant process replacing old bone with new. This complex cellular event involves resorption by osteoclasts and formation of new bone by osteoblasts. The balance between osteoblastic and osteoclastic activity is under regulation by several endocrine and paracrine factors. Osteoprotegerin (OPG), a recently discovered protein is an effective inhibitor of osteociast formation and osteoclast activity. In this thesis, the regulation of OPG mRNA expression and protein secretion from human bone cells has been investigated. Also correlation between a single nucleotide polymorphism in the OPG gene and bone mass has been studied. OPG mRNA levels were affected by several endocrine and paracrine factors known to regulate bone resorption, such as prostaglandin E2, TNFs, interleukin-I and glucocorticoid. An ELISA was developed and it was established that human osteoblasts secrete OPG protein and that the secretion is regulated by the above factors. A single nucleotide polymorphism was discovered in the human OPG gene. There was no correlation between the polymorphism and measures of bone mineral density in a cohort of 1044 post-menopausal females. Surprisingly, a correlation between the polymorphism and measures of vascular function and morphology was discovered. The data in the thesis show that OPG is produced in human bone marrow and is regulated by factors affecting the bone remodeling process, suggesting a central role for OPG in human bone turnover. The finding that the polymorphism in the OPG gene correlates with vascular function opens up a new area of research aiming at understanding whether OPG might be involved also in cardiovascular diseases.