Xian et al. generated knockout mice that were unable to express the receptor for insulin-like growth factor 1 (IGF-1) in their pre-osteoblastic cells to find out more about the impact of IGF-1 on bone remodeling.1 Not surprisingly, as IGF-1 maintains bone mass in adult humans, Igf1r knockout mice had reduced bone mass and lower rates of mineral disposition than controls. This was due to a lower number of mature osteoblasts.
When bone marrow cells were isolated and sorted by flow cytometry, the authors identified cells from the hematopoietic lineage (Sca-1+, CD29+, CD45− and CD11b−). On treatment with rapamycin, an mTOR inhibitor, these cells could not mediate the mineralization normally inducible by IGF-1 but survived and grew normally.
Further experiments revealed that IGF-1 activates mTOR via the IRS1-P13K-Akt pathway and so is able to control the differentiation of osteoblasts, and therefore to regulate bone formation. The authors also demonstrated that the level of IGF-1 in the bone matrix is directly correlated with bone mass.
Editor's comment: This study clearly demonstrates that matrix IGF-1 released during bone remodeling enhances differentiation of pre-osteoblastic cells by stimulating the mTOR pathway. Considering the reported interaction of osteoclast-derived Sema4D with IGF-1 signaling via IRS-1 phosphorylation, this finding suggests that matrix IGF-1 is a key player in maintaining the coupling of bone remodeling.
References
- Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med 2012; e-pub ahead of print 24 June 2012; 10.1038/nm.2793. [DOI] [PMC free article] [PubMed] [Google Scholar]
