Abstract Osteochondromas are the most common skeletal tumors during childhood or adolescence. The tumors grow over time and cause skeletal deformities, nerve compression, pain and other health problems. Osteochondromas are primarily treated surgically and thereby treatment for multiple osteochondromas may require repetitive surgery. Osteochondromas located at a high-risk site for surgery may be managed non- surgically, however, this increases the potential for progression to malignant chondrosarcomas. The final goal of this project is to develop non-surgical therapies that would stop osteochondroma formation and growth in an effective manner. Multiple osteochondromas can be caused by mutations in the heparan sulfate synthases EXT1 or EXT2. Research from our lab and other groups have indicated that reduction in heparan sulfate induce alterations of multiple signaling pathways, leading to osteochondromas. Our long-term studies on nuclear retinoic acid receptor gamma (RARγ) reveal that (1) pharmacologic activation of RARγ strongly inhibits ectopic cartilage formation; (2) RARγ is expressed in cartilage elements in mouse and human osteochondromas; and (3) RARγ agonists inhibited ectopic cartilage formation and induced involution of existing cartilaginous tumor masses in the osteochondroma mouse model. We hypothesize that RARγ could be a novel pharmaco-therapeutic target for osteochondromas by an anti-chondrogenic action and pro- hypertrophic action. The cell origin of osteochondromas remains to be clarified. We have recently discovered a novel cell population of chondroprogenitors contributing to appositional width growth of growth plate. These cells are Wnt-responsive skeletal progenitors and reside in growth plate and the neighboring perichondrium. We hypothesize that aberrant regulation of these progenitors induce osteochondromas and RARγ signaling ameliorates their altered nature. To test these hypotheses, we propose three aims: Aim 1, To establish therapeutic efficacy of RARγ agonists and examine their molecular actions in the mouse osteochondroma model; Aim 2, To determine the cells that contribute to osteochondroma formation and growth and their response to RARγ signaling; and Aim3, To investigate the actions of RARγ agonists on human osteochondroma cells. The study involves diverse experimental procedures encompassing drug treatment with mice, histological and molecular biological assessments of the mouse disease models, high throughput gene expression analysis and study on human tumor cells. The Project will test innovative ideas on the pathogenesis of osteochondroma and equally innovative ideas on how to combat them therapeutically.