Richard Feng

Introduction. Osteoporosis affects over 200 million people worldwide and causes 8.9 million fractures annually.¹ Osteoporosis is characterized by too much bone resorption by osteoclasts with decreased bone formation by osteoblasts.¹ Macrophage and bone mesenchymal stem cell (bMSC) activity is important in the repair of fragility fractures caused by osteoporosis. Fracture healing initially involves a pro-inflammatory state driven by M1 macrophages. Later stages of healing involve an anti-inflammatory state and polarization to M2 macrophages, which communicate with bMSCs via TGF-β, miRNAs, and other cytokines.^2,3 Exosomes serve as the delivery vehicle for miRNA in this crosstalk between macrophages and bMSCs.³ Harnessing these crosstalk molecules may be a potential therapy to treat osteoporosis.  Methods. MSC cultures were treated with M1 and M2 macrophage-derived (M2D) exosomes. Western blotting was then used to measure expression of osteogenic proteins (i.e. collagen I, ALP, Runx2, OCN). Gene ontology enrichment analysis then measured relative miRNA levels in the M1D and M2D exosomes. Mice with femur fractures were injected with M2D exosomes four times over three weeks.³ A second study harvested MSCs from osteoporotic mice and treated them with miRNA-497. Western blotting was conducted from these cultures.⁴ A final clinical research study measured TGF-β serum levels in 65 postmenopausal osteoporotic and 69 postmenopausal non-osteoporotic females. Results. miRNA-5106 from M2 macrophage-derived exosomes were shown to inhibit salt-inducible kinases 2 and 3 (SIK2/SIK3) in MSCs. Doing so releases the inhibition on osteogenic factors such as Runx2, ALP, OCN, and Col1a1, promoting osteogenesis in the setting of a fracture.³ miRNA-497 increased the osteoblast-promoting activity of the TGF-β pathway by binding and preventing translation of leucine-rich alpha-2-glycoprotein 1 (LRG1) mRNA, an inhibitor of the TGF-β pathway.⁴ From the study by Faraji et al., TGF-β serum levels in postmenopausal osteoporotic women were shown to be 23.8 ng/mL compared to 15.8 ng/mL in non-osteoporotic women (P = 0.0009).⁵ Conclusions. miRNA-5106 and miRNA-497 are potential therapeutic targets to stimulate bone formation and fracture healing in osteoporosis where bone mass is lost, given their ability to increase expression of osteogenic proteins through unique pathways. Finally, there is a need to investigate how comorbidities or physiologic alterations impact the mechanism of osteoporosis. Typically, higher levels of TGF-β are thought to increase bone growth, but Faraji et al. found higher TGF-β levels in osteoporotic females than in non-osteoporotic females. Thus, the effects of potential therapies should be researched in the context of many comorbidities to ensure efficacy of treatment.

1.  Muñoz J, Akhavan NS, Mullins AP, Arjmandi BH. Macrophage Polarization and Osteoporosis: A Review. Nutrients. 2020;12(10):2999.
2. Pajarinen J, Lin T, Gibon E, et al. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials. 2019;196:80-89.
3. Xiong Y, Chen L, Yan C, et al. M2 Macrophagy-derived exosomal miRNA-5106 induces bone mesenchymal stem cells towards osteoblastic fate by targeting salt-inducible kinase 2 and 3. J Nanobiotechnology. 2020;18(1):66. Published 2020 Apr 28. doi:10.1186/s12951-020-00622-5
4. Gu Z, Xie D, Huang C, et al. MicroRNA-497 elevation or LRG1 knockdown promotes osteoblast proliferation and collagen synthesis in osteoporosis via TGF-β1/Smads signaling pathway. J Cell Mol Med. 2020;24(21):12619-12632. doi:10.1111/jcmm.15826
5. Faraji A, Abtahi S, Ghaderi A, Samsami Dehaghani A. Transforming Growth Factor β1 (TGF- β1) in the Sera of Postmenopausal Osteoporotic Females. Int J Endocrinol Metab. 2016;14(4):e36511. Published 2016 Oct 22. doi:10.5812/ijem.36511