Insulin-like growth factor I (IGF-1) is a polypeptide with a growth-promoting effect. Its secretory cells are widely distributed in the liver, kidney, heart, lungs, and brain. As a key endocrine pathway, the growth hormone (GH)/IGF-1 signal axis regulates organisms’ growth, development, and aging. Mice with IGF-1 deficiency were born to die, and their bones were stunted. The liver is the main source of systemic IGF-1. However, the specific knockout of IGF-1 in liver cells has little effect on the bone system, but the specific knockout of IGF-1 in osteoblasts (Col1a1-Cre) or chondrocytes (Col2a1-Cre) will lead to a serious reduction in bone mass, indicating that IGF-1 from bone cells has a more important regulatory role on bone growth and development. Because Col1a1-Cre and Col2a1-Cre begin to express at the early stage of embryonic development, it is still unclear which cells regulate bone homeostasis and damage repair by secreting IGF-1 in the adult stage.

On December 28, 2022, YUE Rui's Research Team of the School of Life Sciences and Technology, Tongji University and the Institute of Regenerative Medicine of the Oriental Hospital published a research paper entitled Bone marrow-derived IGF-1 orchestrates maintenance and regeneration of the adult skeleton online in the Proceedings of the National Academy of Sciences of the United States of America (PNAS). Their research discovered that adult bone marrow stromal cells (BMSCs) and megakaryocytes (MKs) expressed IGF-1. In BMSCs, specific knockout of Igf1 results in reduced bone formation, impaired bone repair, and increased bone marrow adipogenesis. In addition, the down-regulation of IGF-1 from BMSCs also mediated the bone marrow fat accumulation induced by fasting. The specific knockout of Igf1 in MKs and platelets (PLTs) produced downstream of MKs results in reduced bone formation and delayed bone repair but does not affect bone marrow adipogenesis. It is particularly important that the platelet-rich plasma (PRP) prepared after knocking out IGF-1 from MKs/PLTs has lost its osteogenic ability, indicating that IGF-1 is the key growth factor in the blood preparation PRP for bone repair. In summary, the research found that BMSCs and MKs/PLTs located in the bone marrow are important cell sources of IGF-1 in the adult skeleton, and revealed the close interaction and dialogue mechanism between the bone and blood system.

YUE Rui's team publishes progress of bone marrow-derived IGF-1 regulating adult skeleton maintenance and damage repair in the Journal of the American Academy of Sciences （PNAS）

The researchers found that BMSCs and MKs in adult mice long bone expressed the highest level of IGF-1 through gene chip and single-cell RNA sequencing analysis. Then, they first hybridized Lepr-Cre with Igf1-flo mice to obtain Lepr-Cre; Igf1f/f mice. MicroCT analysis showed that the bone mass of trabecular bone and cortical bone in knockout mice decreased significantly, and the cortical bone became thinner. Histomorphological analysis showed that the mineral deposition rate, bone formation rate, and the number of osteoblasts in Lepr-Cre; Igf1f/f mice decreased significantly, while the number of osteoclasts remained unchanged. This indicates that IGF-1 from BMSCs promotes bone formation without affecting bone resorption. Next, they conducted femoral drilling and fracture experiments on wild-type and knockout mice. One week and two weeks after the operation, they found that the amount of new bone in the injured part of knockout mice was significantly reduced. The data shows that IGF-1 from BMSCs promotes bone formation and bone repair.The researchers also analyzed the bone marrow fat phenotype of knockout mice. Compared with the control group, the number of bone marrow fat in Lepr-Cre; Igf1f/f mice was significantly increased, and the adipogenic differentiation of BMSCs in vitro was also significantly enhanced, indicating that IGF-1 derived from BMSCs inhibited bone marrow fat formation. Interestingly, fasting for 48 hours would increase the number of bone marrow fat in wild-type mice, but could not significantly increase the number of bone marrow adipocytes in Lepr-Cre; gf1f/f mice, which suggested that the down-regulation of IGF-1 derived from BMSCs mediated the bone marrow fat accumulation induced by fasting. ELISA results showed that the plasma IGF-1 levels of Lepr-Cre; Igf1f/f mice and wild-type mice are similar, and both significantly down-regulated after fasting, suggesting that the phenomenon above is a local regulation of bone marrow.

Next, researchers hybridized Pf4-Cre mice with Igf1-flox mice to obtain Pf4-Cre; Igf1f/f mice. Interestingly, the femur of Pf4-Cre; Igf1f/f adult mice also showed a phenotype of decreased bone mass, decreased bone formation, and decreased number of osteoblasts but unchanged osteoclasts. In addition, Pf4-Cre; Igf1f/f mice also showed the phenotype of delayed bone repair in femoral perforation and fracture experiments. ELISA results showed the level of IGF-1 in the plasma of Pf4-Cre; Igf1f/f mice decreased by about 35%, indicating that MKs/PLTs were another systemic source of IGF-1 besides the liver, and regulated bone maintenance and repair in a paracrine/endocrine manner. Finally, they also found that the treatment group‘s new bone transplanted with platelet-rich plasma (PRP) from wild-type mice increased significantly, but the transplanted bone from Pf4-cre; IGF-1 from MKs/PLTs did not vary significantly from that of the control group. The result showed that IGF-1 from MKs/PLTs is the key factor for PRP to promote bone regeneration.In general, this study explored the regulatory role of IGF-1 derived from BMSCs and MKs/PLTs on the maintenance of adult skeleton homeostasis and damage repair. IGF-1 from BMSCs balances osteogenesis and adipogenic differentiation under steady and stress states in an autocrine manner, while IGF-1 from MKs/PLTs regulates bone homeostasis and bone repair in a paracrine/endocrine manner. This research result not only emphasizes the importance of bone marrow-derived IGF-1 for the maintenance and regeneration of the adult skeleton, but also finds a new molecular mechanism for the dialogue between the bone and blood system, and lays a theoretical foundation for the optimization and application of blood products promoting bone repair.