Regulation of patterning and morphogenesis during embryonic development depends on tissue-specific signaling by retinoic acid (RA), the active form of Vitamin A (retinol). The first enzymatic step in RA synthesis, the oxidation of retinol to retinal, is thought to be carried out by the ubiquitous or overlapping activities of redundant alcohol dehydrogenases. The second oxidation step, the conversion of retinal to RA, is performed by retinaldehyde dehydrogenases. Thus, the specific spatiotemporal distribution of retinoid synthesis is believed to be controlled exclusively at the level of the second oxidation reaction. In an N-ethyl-N-nitrosourea (ENU)-induced forward genetic screen we discovered a new midgestation lethal mouse mutant, called trex, which displays craniofacial, limb, and organ abnormalities. The trex phenotype is caused by a mutation in the short-chain dehydrogenase/reductase, RDH10. Using protein modeling, enzymatic assays, and mutant embryos, we determined that RDH10^trex mutant protein lacks the ability to oxidize retinol to retinal, resulting in insufficient RA signaling. Thus, we show that the first oxidative step of Vitamin A metabolism, which is catalyzed in large part by the retinol dehydrogenase RDH10, is critical for the spatiotemporal synthesis of RA. Furthermore, these results identify a new nodal point in RA metabolism during embryogenesis.

Significance: Osteoarthritis is a common debilitating joint disease that affects millions in the United States and for which there are few therapeutic options. Critical barriers to the successful development of osteoarthritis treatment include limited understanding of the pathways governing early cartilage degradation and ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Using a peptidic nanoparticle carrying siRNA that specifically suppresses NF-κB, we show that early antiinflammatory intervention reduces chondrocyte death caused by joint injury, a known predisposing factor for osteoarthritis. The peptidic nanoparticle deeply penetrates human cartilage to deliver its therapeutic cargo to the chondrocytes, demonstrating its ability to permeate the dense cartilage matrix. This approach promises to overcome the barriers to effectively treat osteoarthritis.