Anti-diabetic drug metformin has been shown to enhance osteoblasts differentiation and inhibit osteoclast differentiation in vitro and prevent bone loss in ovariectomized (OVX) rats. But the mechanisms through which metformin regulates osteoclastogensis are not known. Osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) are cytokines predominantly secreted by osteoblasts and play critical roles in the differentiation and function of osteoclasts. In this study, we demonstrated that metformin dose-dependently stimulated OPG and reduced RANKL mRNA and protein expression in mouse calvarial osteoblasts and osteoblastic cell line MC3T3-E1. Inhibition of AMP-activated protein kinase (AMPK) and CaM kinase kinase (CaMKK), two targets of metformin, suppressed endogenous and metformin-induced OPG secretion in osteoblasts. Moreover, supernatant of osteoblasts treated with metformin reduced formation of tartrate resistant acid phosphatase (TRAP)-positive multi-nucleated cells in Raw264.7 cells. Most importantly, metformin significantly increased total body bone mineral density, prevented bone loss and decreased TRAP-positive cells in OVX rats proximal tibiae, accompanied with an increase of OPG and decrease of RANKL expression. These in vivo and in vitro studies suggest that metformin reduces RANKL and stimulates OPG expression in osteoblasts, further inhibits osteoclast differentiation and prevents bone loss in OVX rats.

Oleanolic acid (OA), a pentacyclic triterpenoid exhibits potent anti-tumor activity against many tumor cell lines. But the mechanisms through which OA inhibits osteosarcoma cells are not known. The mammalian target of rapamycin (mTOR) serves as a central regulator of cell growth, proliferation, survival, and metabolism by integrating intracellular and extracellular signals. In this study, we examined effects of OA on proliferation, cell cycle progression, apoptosis in osteosarcoma cells, and involvement of mTOR signaling in this process. OA inhibited cell proliferation and colony formation, induced G1 arrest in osteosarcoma MG63 and Saos-2 cells dose and time dependently. The protein level of cyclin D1, which plays critical role in G1 to S phase transition and servers as a downstream target of mTOR complex 1 (mTORC1) was down-regulated by OA. Phosphorylation of p70 ribosomal S6 kinase 1 (p70 S6K1) (T389) and S6 (S235/236), mediators of mTORC1 signaling in controlling protein translation and cell growth, was also inhibited by OA. Furthermore, OA inhibited phosphorylation of Akt, a pro-survival factor and substrate for mTORC2. Inactivation of Akt correlated with pro-apoptotic role of OA in osteosarcoma cells, as manifested by an increase in annexin V-FITC binding, cleavage of poly (ADP-ribose) polymerase (PARP) and activation of caspases 3. Our results suggest that OA is a promising agent for treatment of osteosarcoma and mTOR signaling may contribute to its anti-tumor effects on osteosarcoma cells. ß

BackgroundThis study aimed to evaluate outcome following a single lateral rectus abdominis surgical approach for complicated acetabular fractures, involving anterior and posterior columns.Material/MethodsFrom January 2012 to March 2016, 59 patients, including 36 anterior column hemitransverse fractures, 18 two-column fractures, and five T-type complicated acetabular fractures, were treated with a single lateral rectus abdominis approach and fixed by plates and cannulated lag screws. Anterior column fractures were fixed with 3.5 mm reconstruction plates; posterior column fractures were fixed with 6.5 mm cannulated lag screws. The quality of surgical reduction (using the Matta criteria), functional outcome (using the modified Merle d’Aubigné and Postel scoring system), and postoperative complications were assessed with 24-month follow-up.ResultsFifty-nine patients (mean age, 45 years; range, 18–64 years) including 39 men and 20 women underwent surgery. Mean intraoperative blood loss was 514.6 ml (range, 150–830 ml) and mean operating time was 86.3 min (range, 42–145 min). Anatomical reduction was good in 40 cases (67.8%), fair in 15 cases (25.4%), and poor in four cases (6.8%). The modified Merle d’Aubigné score was excellent in 39 cases (66.1%), good in 14 cases (23.7%), fair in five cases (8.5%), and poor in one case (1.7%). At follow-up, there were five cases of peritoneal damage, eight cases of obturator nerve dysfunction, and four cases of postoperative traumatic arthritis.ConclusionsThe single lateral rectus abdominis surgical approach for the treatment of complicated acetabular fractures was minimally invasive with good anatomical exposure and good outcomes.

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