Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, United States; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
Yilin Yu
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
Yunji Zhou
Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, United States
Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, United States
Guo-Fang Zhang
Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States; Department of Medicine, Duke University School of Medicine, Durham, United States
Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, United States; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, Dallas, United States
Cellular differentiation is associated with the acquisition of a unique protein signature that is essential to attain the ultimate cellular function and activity of the differentiated cell. This is predicted to result in unique biosynthetic demands that arise during differentiation. Using a bioinformatic approach, we discovered that osteoblast differentiation is associated with increased demand for the amino acid proline. When compared to other differentiated cells, osteoblast-associated proteins, including RUNX2, OSX, OCN, and COL1A1, are significantly enriched in proline. Using a genetic and metabolomic approach, we demonstrate that the neutral amino acid transporter SLC38A2 acts cell-autonomously to provide proline to facilitate the efficient synthesis of proline-rich osteoblast proteins. Genetic ablation of SLC38A2 in osteoblasts limits both osteoblast differentiation and bone formation in mice. Mechanistically, proline is primarily incorporated into nascent protein with little metabolism observed. Collectively, these data highlight a requirement for proline in fulfilling the unique biosynthetic requirements that arise during osteoblast differentiation and bone formation.
