Grant: Operating Grant

Hyaluronan is a polysaccharide present throughout the body, but is particularly abundant in the skeletal system, where it is essential for the normal structure and function of the cartilage models that form the long bones and vertebrae, and for regulating the metabolic activity of their constituent cells, the chondrocytes. Prevention of hyaluronan synthesis in cartilage during fetal development results in a neonatal lethal dwarfism, in which the formation and growth of all bones derived from cartilage are abnormal. This implies that depletion of hyaluronan not only impairs chondrocyte metabolism and cartilage function, but also prevents the normal formation and subsequent modeling of the resulting bone by its constituent cells, the osteoblasts and osteoclasts. The current proposal is designed to extend these observations from the fetus to post-natal life, and to evaluate how hyaluronan influences the formation of bones such as the skull that are not derived from cartilage. This will allow us to understand whether hyaluronan deficiency in the growth plates of juvenile bones will impair growth, whether hyaluronan deficiency in the articular cartilage of the joints will promote the onset of degenerative arthritis, and whether hyaluronan deficiency in skull will prevent its normal formation. It will also determine the mechanism by which hyaluronan depletion exerts its effect on the different cell types. Understanding how hyaluronan deficiency leads to the formation of abnormal cartilage and bone is a prerequisite for determining whether hyaluronan administration can be used as a therapeutic strategy in conditions where cartilage and bone formation and function are impaired, such as in aberrant fracture healing.