Genetic Deficiency of Hyaluronan Synthase 2 in the Developing Limb Mesenchyme Impairs Postnatal Synovial Joint Formation

Hyaluronan, a key component of the extracellular matrix, plays a crucial role in joint development and maintenance. In order to determine the role of hyaluronan function in joint development and homeostasis, conditional loss-of-function experiments of Hyaluronan Synthase 2 (<i>Has2</i>) were carried out in mice. <i>Has2</i> depletion in limb mesenchymal cells led to severely shortened limbs with appendicular joints that are deformed, decreased proteoglycan content as characterized by Safranin-O staining, and severely pitted epiphyseal ends of long bones and deformed joints as viewed by micro-CT reconstructions. The embryonic deletion of <i>Has2</i> in mesoderm mesenchyme of limbs by Prx1-Cre confirmed its involvement in joint development, while in situ hybridization and hyaluronan staining confirmed <i>Has2</i> expression and abundant accumulation of hyaluronan in the onset of joint formation, the joint interzone. These findings position <i>Has2</i> as the main hyaluronan-making enzyme in articular cartilage and highlight its essential function in joint formation and retention of proteoglycans of the extracellular matrix of the cartilage.