Mutations in COL2A1 produce a spectrum of disorders whose hallmark feature is alterations in skeletal development. Attempts to counteract the effects of collagen mutations at the molecular level have been relatively ineffective due to the inability to selectively suppress a mutant allele, and failure to deliver a sufficient number of cells expressing wild‐type collagen. Moreover, these approaches are hampered because the minimal therapeutic conditions that would allow extracellular matrix remodeling and recovery of cells from stress are not known. Here, we employed a tetracycline‐inducible system for expressing the R789C or R992C collagen II mutants, allowing us to decrease the production of mutant proteins by 25, 50, 75, or 100% with respect to their initial production. Through analysis of intracellular and extracellular parameters we have shown that affected cell/matrix systems are able to recover from mutation‐induced aberrations only when 100% expression of mutant collagens is shut off, but not if the expression of small amounts of mutant molecules persists in the system. Our data suggest that efficient remodeling of tissues affected by the presence of thermolabile collagen mutants may depend on their complete elimination rather than on partial reduction. Hum Mutat 32:1–12, 2011. © 2011 Wiley‐Liss, Inc.