Ice have been characterized by dwarfism involving elongation from the growth plate proliferative zone and delayed chondrocyte hypertrophy [16]. Proliferative zone elongation in these mice was on account of reduced expression within the pre-hypertrophic zone of p57Kip2, a gene identified as a transcriptional target of C/EBP- that encodes a cyclin-dependent kinase inhibitor important for the exit of chondrocytes from cell division [16,35]. Along with driving the expression of p57Kip2, C/EBP- represses the expression of Sox9 and Col2a1, each crucial markers of chondrocyte proliferation [18]. As a result, C/EBP- appears to have dual roles as a transcription aspect controlling chondrocyte proliferation, switching off the expression of genes involved in maintaining the proliferative phenotype and switching around the expression of genes involved in terminating chondrocyte proliferation. As well as promoting the exit of chondrocytes from their proliferative plan, C/EBP- also actively promotes the entry of chondrocytes into hypertrophy. It has been shown that C/ EBP- co-localizes within the development plate hypertrophic zone with GADD45- and collagen X [20], and that it acts cooperatively with GADD45- to regulate Col10a1 and Mmp13 expression [20,21]. MMP13 is critical for endochondral ossification, because Mmp13-null mice are characterized by hypertrophic zone expansion, decreased collagen turnover, and delayed ossification [36]. Along with GADD45-, RUNX2 has also been implicated as a transcriptional co-factor of C/EBP-. The Cebpb-/- mouse dwarfism phenotype was substantially exacerbated when crossed with a heterozygous Runx2 knockout mouse to generate Cebpb-/-;Runx2+/-, in which impaired cartilage remodelling by means of loss of Mmp13 expression resulted in elongation on the hypertrophic zone, in addition to the elongated proliferative zone noticed in Cebpb-/- [17]. Hence, C/EBP- actively promotes chondrocyte hypertrophy and development plate matrix remodelling and turnover by interacting cooperatively with GADD45- and RUNX2 to drive the expression of crucial markers of terminal chondrocyte maturation such as Col10a1 and Mmp13. Histomorphometric and expression profiling data in this and previous studies [11,12,27] are constant with inhibition of C/EBP- activity in ColXN617K and C/X growth plates. The hypertrophic zone expansion we have observed in ColXN617K [11,12] and C/X, the Reversine site manner in which development plate zone gene signatures were dysregulated in ColXN617K and C/X, and the down-regulation of important C/EBP- transcriptional targets, p57Kip2, Col10a1, and Mmp13 observed here and previously [27] are all highly reminiscent of the skeletal phenotypes reported for the Cebpb-/- and Cebpb-/-;Runx2+/- mice [16,17]. In addition, the mis-expression of SOX9 and Col2a1 in the 13del collagen X transgenic mouse is constant with suppressed C/EBP- activity inside the MCDS growth plate [27]. Crucially however, the expression of Cebpb itself was not substantially down-regulated in the hypertrophic zones of either ColXN617K or C/X, implying that disruption to C/EBP- activity in these mice must have occurred posttranscriptionally. The down-regulation of Gadd45b and Runx2 that we observed in ColXN617KPLOS Genetics | DOI:10.1371/journal.pgen.September 15,15 /XBP1-Independent UPR Causes Pathology inside a Collagen X Chondrodysplasiaand C/X relative to their controls is expected to have depleted the availability of C/EBP- transcriptional co-factors required to promote hypertrophy in these mutants, and may possibly hence have contr.