Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism

J Clin Invest. 2017 Jun 30;127(7):2612-2625. doi: 10.1172/JCI92233. Epub 2017 Jun 5.


Cleidocranial dysplasia (CCD) is an autosomal dominant human disorder characterized by abnormal bone development that is mainly due to defective intramembranous bone formation by osteoblasts. Here, we describe a mouse strain lacking the E3 ubiquitin ligase RNF146 that shows phenotypic similarities to CCD. Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of WNT3a-induced β-catenin activation and reduced Fgf18 expression in osteoblasts. We show that FGF18 induces transcriptional coactivator with PDZ-binding motif (TAZ) expression, which is required for osteoblast proliferation and differentiation through transcriptional enhancer associate domain (TEAD) and runt-related transcription factor 2 (RUNX2) transcription factors, respectively. Finally, we demonstrate that adipogenesis is enhanced in Rnf146-/- mouse embryonic fibroblasts. Moreover, mice with loss of RNF146 within the osteoblast lineage had increased fat stores and were glucose intolerant with severe osteopenia because of defective osteoblastogenesis and subsequent impaired osteocalcin production. These findings indicate that RNF146 is required to coordinate β-catenin signaling within the osteoblast lineage during embryonic and postnatal bone development.

MeSH terms

  • Animals
  • Axin Protein / biosynthesis
  • Axin Protein / genetics
  • Bone Development*
  • Cleidocranial Dysplasia / genetics
  • Cleidocranial Dysplasia / metabolism*
  • Core Binding Factor Alpha 1 Subunit / biosynthesis
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Energy Metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Osteoblasts / metabolism*
  • Osteocalcin / biosynthesis
  • Osteocalcin / genetics
  • Signal Transduction*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Axin Protein
  • Axin1 protein, mouse
  • Core Binding Factor Alpha 1 Subunit
  • Runx2 protein, mouse
  • beta Catenin
  • Osteocalcin
  • Rnf146 protein, mouse
  • Ubiquitin-Protein Ligases