Bone growth and metabolism is precisely regulated by two types of cells: osteoblasts, which form new bone tissue, and osteoclasts, which resorb old bone tissue. The complicated interaction between osteoblasts and osteoclasts makes the bone remodeling in a dynamic balance, which is crucial for homeostasis of the skeletal system. The disequilibration between these two cell types will lead to bone diseases such as osteoporosis.
The incidence of degenerative bone diseases is very high. Although they have been widely used in clinical, pyrophosphate and other drugs can only specifically inhibit osteoclast-mediated bone resorption, and can’t play a major role in improving bone formation or bone remodeling. So it will be conducive to the clinical treatment of osteoporosis by further strengthening the orthopedic fundamental research.
A new study conducted by Dr. ZOU Weiguo’s group at the Institute of Biochemistry and Cell Biology of Chinese Academy of Sciences revealed that ubiquitin E3 ligase SMURF2 maintains bone homeostasis by regulating the vitamin D receptor (VDR) signaling in osteoblasts. This study is a new discovery in basic research of orthopedic related disease and was published in Nature Communications.
SMURF2 belongs to the Neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) family. Related proteins in this family have similar structures. All of them contain a catalytic HECT domain at the C-terminus, and an N-terminal region including a C2 domain and a series of WW domains.
SMURF1 and SMURF2 are highly homologous proteins. According to the previous study, Smurf1-/- mice display increased bone formation and bone mass. Researchers identified that SMURF1 and SMURF2 have a similar effect on osteoblast differentiation, but mice lacking SMURF2 have low bone mass, opposite to the phenotype of Smurf1-deficient mice. Smurf2-/- mice have an increase in osteoclast numbers and bone resorption, which is similar to osteoporosis symptoms.
Further studies show that SMURF2 regulates Tumor Necrosis Factor Superfamily Member 11 (RANKL) expression in osteoblasts by affecting the interaction between SMAD3 and VDR. To identify the function of SMURF2 in osteoblasts, researchers constructed Smurf2 osteoblast-lineage conditional knockout mice (prx1-Cre, Smurf2fl/fl). The bone phenotype of Smurf2 conditional knockout mice, showing increased RANKL expression, enhanced osteoclast differentiation and decreased bone mineral density, was similar to that of germline Smurf2-/-mice.
This study focused on the molecular mechanisms of skeletal system stability and indicated that SMURF2 is a key factor in the process. Also, the relevant data showed that bone remodeling and bone mineral density can be regulated by adjusting the activity of SMURF2 and interrupting the interaction between SMAD3 and VDR in osteoblasts.
This work was supported by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology of China and the Chinese Academy of Sciences.
Figure: A and B: Smurf2-/- mice have low bone mass, C: SMURF2 regulates RANKL expression by adjusting the interaction between SMAD3 and VDR. (Image by ZOU Weiguo's group)
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