Growth plate and long bone development isgoverned by biochemical signaling pathways of which thePTHrP–Ihh system is the best known. Other factors, such asBMPs, FGFs and mechanical loading, may interact with thissystem. This study aims at elucidating the relative importanceof PTHrP and Ihh for controlling proliferation, and hypertrophyin fetal growth plate cartilage. We assessed the questionwhy reduced Ihh expression leads to more pronounced effectson the number of non-hypertrophic cells and total boneformation, compared to PTHrP down-regulation.Using few basic equations, constituted from literaturedata, this paper shows how the PTHrP–Ihh feedback systemcan control different aspects of tissue differentiation atdistinct locations. In particular, it is shown that (mechanicalor biochemical) perturbations will affect proliferation viaIhh-related parameters, whereas changes in PTHrP-relatedparameters selectively interact with hypertrophy. This is contra-intuitive, since PTHrP acts to keep cells proliferating. Inthis context, the critical PTHrP level for keeping cells proliferatinghas been reconsidered. In addition, an explanation isprovided for the aforementioned difference in effect between reduced Ihh and PTHrP expression.