Mechanisms of bone anabolism regulated by statins

Abstract

Osteoporosis is a common disease in the elderly population. The progress of this disease results in the reduction of bone mass and can increase the incidence of fractures. Drugs presently used clinically can block the aggravation of this disease. However, these drugs cannot increase the bone mass and may result in certain side effects. Statins, also known as HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, have been widely prescribed for CVD (cardiovascular disease) for decades. Nonetheless, several studies have demonstrated that statins exert bone anabolic effect and may be helpful for the treatment of osteoporosis. Several experiments have analysed the mechanisms of bone anabolism regulated by statins. In the present paper, we review the mechanisms of promoting osteogenesis, suppressing osteoblast apoptosis and inhibiting osteoclastogenesis.

Figure 1. Biosynthetic route of endogenous cholesterol synthesis

Statins competitively inhibit HMG-CoA reductase and thereby inhibit the synthesis of mevalonic acid. FPP is the downstream mediator of mevalonic acid. Therefore the synthesis of FPP can be blocked by statins. Squalene synthase catalyses FPP to form squalene and then squalene is converted into cholesterol through multiple reactions. FPP can also be covalently added to small G-proteins to produce farnesylated proteins. This process is catalysed by farnesyl transferase (FT) and can be inhibited by an FT inhibitor (FTI). GGPPs converts FPP into GGPP. GGPPs can be inhibited by DGBP. Geranylgeranyl transferase (GT) transfers the geranylgeranyl moiety of GGPP to the small G-proteins to produce geranylgeranyl proteins.

Figure 2. The signal pathway for bone anabolic effect induced by statins

Statins activate Ras by inhibiting the synthesis of FPP, and then stimulate the expression of BMP-2 through the PI3K/Akt/MAPK pathway. BMP-2 up-regulates the expression of the Runx2 gene, and phosphorylated Runx2 stimulates a series of bone-specific gene transcriptions and promotes the differentiation of osteoblasts. The inhibition FPP synthesis inactivates Rho and MKP-1 by decreasing GR production, which abolishes the negative effects of Rho and MKP-1 on osteogenesis. FPP is a transcriptional activator of GR that activates MKP-1 to dephosphorylate MAPKs, and GGPP converted from FPP inhibits the differentiation of osteoblasts by activating Rho. Statins inhibit osteoblast apoptosis by stimulating Smad3. In addition, statins regulate the OPG/RANKL/RANK signalling pathway by increasing the expression of ER, thereby inhibiting osteoclastogenesis.