Impact of Cigarette Smoking on Fracture Repair Project Overview A large body of clinical data establishes that fracture healing is impaired/delayed in cigarette smokers. While there are several potential reasons for this, we have focused our attention on the influence of smoke on the initial phase of repair: the chondrogenesis/chondrocyte differentiation phase. Two key components in smoke that enter the bloodstream and can have direct effects on cells at the fracture site are nicotine and polycyclic aromatic hydrocarbons. We have examined the influence of these compounds during initial healing at the chondrogenic commitment phase, and have discovered that both influence the formation of cartilage callus via nicotinic acetylcholine receptor signaling and aryl hydrocarbon receptor signaling respectively. Both of these receptors are expressed in chondro-progenitor cells and are critical regulators of the genetic program required for chondrocyte differentiation to be initiated. Our effort to tease out the specific contribution of each pathway to early fracture healing, which involves genetic approaches and mouse models, will enable us to educate smokers about the negative effects of cigarettes on the repair process and drive the development of strategies to mitigate the deleterious effect of smoking on overall healing.