Osteoporosis is a major bone-turnover disorder which can commonly affect the elderly and postmenopausal women (Chang et al., 2016). Although the “bone density” which reflects bone mass is an important quantitative indicator when diagnosing osteoporosis, the critical significance of osteoporosis in the clinical practice is that, this population is prone to fractures, leading to both increased disability and death. In addition to bone mass, bone quality and other non-skeletal factors can also be considered as potential risk factors for fractures (Martin and Correa, 2010).

Osteoporosis is primarily an age-related bone disease, which has emerged as a worldwide public health problem (Rajasree Vijayakumar, 2016). It has been reported that more than 9.9 million Americans suffer from osteoporosis (Wright et al., 2014). The incidence of fragility fractures is 50% in women and 20% in men (Cummings and Melton, 2002). The recurrence incidence was reported to be 2.12% in the first year, and 4.66% in the first 2 years (Ruan et al., 2011). Treatment and care after the fractures can cause heavy economic and spiritual burdens on the family. Statistical data has revealed that within 1 year after the hip fractures, approximately 20% of patients died with various complications, about 50% were disabled, and the quality of life was significantly reduced (Lin et al., 2014). Osteoporosis often can exhibit the symptoms of joint pain. At the same time, the patients with degenerative joint disease are often affected with osteoporosis. Osteoporosis and osteoarthropathy can arise as a result of certain potential shared mechanisms (Hart et al., 1994; Shen et al., 2013; Im and Kim, 2014; Geusens and van den Bergh, 2016).

There are currently no treatment modalities that can be used for the complete cure of osteoporosis. There are mainly two types of drugs used for the management of osteoporosis: bone formation promotors and resorption inhibitors. Most of the existing clinical drugs are bone resorption inhibitors. Hence, we need to identify and develop novel drugs, which can promote bone formation. Tanshinone, a traditional Chinese medicine, has been used clinically as a drug for the treatment of various chronic diseases (Kim et al., 2016; Li et al., 2016). Moreover, previous studies have shown that tanshinone can also exhibit the potential of both decreasing apoptosis of osteoblasts and promoting osteogenesis (Kim et al., 2004; Baker et al., 2015; Cheng et al., 2018; Zhu et al., 2018; Zhang et al., 2020). Bioinformatics analysis has been used in some previous studies to explore the mechanism of dugs or formulations on the various diseases (Mi et al., 2020a; Xiong et al., 2020a). Therefore, this research aimed to investigate the underlying mechanism of tanshinone in the treatment of osteoporosis through using bioinformatics analysis, followed by verification of the findings through some laboratory experiments.

Bones play an important role in the protection of internal organs with both rigidity and toughness. The repeated bone reconstruction process primarily maintains integrity and mechanical stress of bone. Bone reconstruction includes resorption of old bone and formation of new bone, which are generally coupled in time and space. Bone reconstruction occurs every moment, throughout the life of a mammal, and the whole body bones are renewed every 10 years (Szulc, 2018).

Bone reconstruction is orchestrated by osteoblast, osteocyte and osteoclast mutually (Xiong et al., 2020b). Osteoblasts produce type I collagen to form a mineralized matrix. The old bone resorption caused by osteoclasts is replaced by new bone formation promoted by osteoblasts. Osteocytes are ultimately differentiated by osteoblasts and embedded in the mineralized matrix (Florencio-Silva et al., 2015). Bone cells can perceive new signals whenever there are changes in the external environment of cells, communicate with osteoblasts and osteoclasts on the bone surface, guide osteoclasts and osteoblasts to the reconstruction site, regulate bone reconstruction, and thus effectively promote repair of microfractures (Buck and Dumanian, 2012). In adolescents, the rate of bone formation has been found to be greater than the resorption. The bones are constantly built, shaped and reconstructed, which can lead to an increase in bone mass. Bone resorption and formation are balanced in adulthood to maintain bone mass. In the elderly, bone resorption rate is greater than formation rate, and osteoporosis begins to occur. In osteoporosis patients, bone mass and strength decreases significantly whereas fracture risk can potentially increase (Feng and McDonald, 2011). Senile osteoporosis presents low bone turnover, but the ratio of bone resorption/bone formation increases, thus leading to progressive bone loss. At the same time, aging and estrogen deficiency can cause the immune system to initiate pro-inflammatory reactions and thereby affect bone reconstruction. Vitamin D deficiency and negative calcium balance in the elderly can also lead to the secondary hyperparathyroidism and affect bone mass (Feng and McDonald, 2011).

The bone reconstruction is in a dynamic equilibrium state under the action of the various systemic or local bone growth regulators. A variety of signal transduction pathways have been reported to be involved in regulating bone reconstruction, such as Hedgehog, MAPK, Notch, RANKL/RANK/OPG, PI3K/Akt, and Wnt/β-catenin pathways (Boyce and Xing, 2007; Greenblatt et al., 2010; Regan and Long, 2013; Xi et al., 2015; Yang et al., 2015; Duan and Bonewald, 2016; Mi et al., 2020b). In our study, we found that tanshinone could exhibit a variety of cellular activities through modulating MAPK, PI3K/Akt, and p53 signaling pathways. In the tanshinone-targeted genes network, AKT1 displayed the greatest degree, betweenness, and closeness. Therefore, for the further validation experiments, it was demonstrated that tanshinone could modulate AKT1 gene expression, promote the MSCs proliferation, and suppress their apoptosis. These findings indicated that tanshinone might improve osteoporosis by targeting AKT1.

There are some limitations associated with this study. Firstly, in vivo experiments were not performed in this study. Secondly, the enrichment test of AKT1 in different osteoporosis subtypes was not studied.

Taken together, our findings indicate that tanshinone can alleviate osteoporosis, which was potentially mediated through modulation of the AKT1 expression. Tanshinone could thus serve as a promising agent for the treatment of osteoporosis.