Osteoblasts and adipocytes are derived from a common precursor, bone marrow mesenchymal stem cells (MSCs). The choice of MSCs to become either osteoblasts or adipocytes is believed to be involved in the manifestation of various metabolic disorders, such as obesity, osteoporosis and osteopetrosis. However, the mechanism controlling the balance between osteogenesis and adipogenesis is unclear.

A research team led by Drs. SHI Yufang and WANG Ying at the Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and School of Medicine of Shanghai Jiao Tong University found that, me^v/me^v mice, whose SH2 domain-containing phosphatase 1 (SHP1) gene only maintains 25% activity, spontaneously developed osteoporosis. Consistently, MSCs from me^v/me^v mice exhibited a significant reduction in osteoblast differentiation and a robust increase in adipocyte differentiation.

This finding was verified in SHP1 knock-down MSCs and MSCs with the addition of SHP-1 inhibitor. When SHP1 deficiency MSCs was implanted in vivo with hydroxyapatite tricalcium phosphate, there was less bone formation as compared with wild type MSCs.

At the molecular level, SHP1 was found to bind to Glycogen synthase kinase 3 (GSK3b) and suppress its kinase activity by dephosphorylating pY216, thus leading to b-catenin stabilization. Interestingly, researchers found that SHP1^fl/flDermo1-Cre mice, losing SHP1 activity specifically in MSCs, showed reduced bone mass and enhanced adipose tissue content.

Taking together, this study reveals a novel role of SHP1 in controlling MSC differentiation and could have important ramifications in the management of metabolic diseases.

The study entitled “SHP1 Regulates Bone Mass by Directing Mesenchymal Stem Cell Differentiation” has been published in Cell Reports.

This work was supported by the Ministry of Science and Technology of China, National Natural Science Foundation of China and Chinese Academy of Sciences.

Figure: Mechanisms of SHP1 dictating MSC differentiation (Image by JIANG Menghui from Prof. SHI Yufang’s group)