The Role Of Wnt Signaling In Cartilage Development

Wnt signaling plays an important role in the regulation of cartilagedevelopment. Wnt protein family has19members. Redundant anddistinct roles have been identified among these Wnt proteins. Wls is aconserved membrane protein dedicated to the secretion of Wnt proteins.Loss of Wls function blocks the Wnt secretion, causes accumulation ofWnt proteins in the cell, and thus blocks the activity of Wnt signalingpathway.To investigate the function of chondrocyte-derived Wnts in theregulation of cartilage development, we generated Col2-Cre;Wlsc/cconditional knockout mouse, which blocks the Wnt secretion and itsnormal function in cartilage and perichondrium. The endochondralossification is impaired in the Col2-Cre;Wlsc/cmice. In the knockout mice,chondrocyte hypertrophy is delayed, ectopic cartilage is formed in theperichondrium at the cost of osteoblast differentiation, and chondrocyteproliferation is down regulated. The proliferating chondrocytes in the Col2-Cre;Wlsc/cembryos haveexhibited altered morphology and polarity, which lost the columnararrangement and are not as flat as those in the wild types. The orientedcell division of the proliferating chondrocytes is also disrupted in themutant embryos.To investigate the paracrine effect of Wnt proteins from the bone inthe regulation of cartilage development, we have also generated theCol1-Cre;Wlsc/cconditional knockout mice, which blocks the Wntsecretion in the osteoblasts. Inactivation of Wls in osteoblasts increasedthe number of TRAP positive cells, and decreased the width ofhypertrophic chondrocyte zone, coupled with a decrease in bone mass.Taken together, our studies reveal that Wnt proteins not onlyregulate differentiation and cellular communication within populations ofchondrocytes, but also mediate the reciprocal crosstalk between thechondrocytes and osteoblasts in the growth plate. In addition, we alsoanalyzed the structure and fucntion of Sost protein through assessing theeffect of point mutation on luciferase induction in response to Wntstimulation.