Accumulating evidence indicates that intracellular reactive oxygen species (ROS) production is highly involved in bone homeostasis by intervening osteoclast or osteoblast differentiation. Interestingly, ROS that are known as oxidizing agents exert dose-dependent biphasic properties in bone remodeling, including preventing osteoblast activity but accelerating osteoclast resorption. ROS mainly composed of superoxide anion radical, hydroxyl radical, nitric oxide, and two-electron reduction product hydrogen peroxide, which are important components to regulate bone cell metabolism and function in mammal skeleton. These free radicals can be partly produced in bone and boosted in an inflammation state. Although numerous researches have emphasized the impacts of ROS on bone cell biology and verified the mechanism of ROS signaling cascades, the recapitulatory commentary is necessary. In this review article, we particularly focus on the regulation of the intracellular ROS and its potential mechanism impacting on cell-signaling transduction in osteoclast and osteoblast differentiation for preferable understanding the pathogenesis and searching for novel therapeutic protocols for human bone diseases.

Bone mass loss around prostheses is a major cause of implant failure, especially in postmenopausal osteoporosis patients. In osteoporosis, excess oxidative stress largely contributed abnormal bone remodeling. Melatonin, which is synthesized from the pineal gland, promotes osteoblast differentiation and bone formation and has effectively been used to combat oxidative stress. Thus, we determined if melatonin can inhibit oxidative stress to promote osteogenesis and improve bone mass around prostheses in osteoporosis. In this study, we observed that received melatonin at 50 mg/kg body weight significantly increased periprosthetic bone mass as well as implant fixation intensity in ovariectomized (OVX) rats. Meanwhile, it decreased the expression of oxidative stress markers (NAPDH oxidase 2 and cytochrome c) and enhanced expressing level of the formation markers of bones (alkaline phosphatase, osteocalcin, and osterix) around prostheses compared to that in the control group. Additionally, melatonin decreased hydrogen peroxide- (H2O2-) induced oxidative stress and restored the osteogenesis potential of MC3T3-E1 cells. Mechanistically, melatonin clearly increased mitochondrial sirtuin 3 (SIRT3) expression and decreased the ratio of acetylated superoxide dismutase 2 (AC-SOD2)/SOD2 compared to the H2O2 group. SIRT3 inhibition counteracted the protective effects of melatonin on oxidative stress and bone formation. Together, the results showed that melatonin ameliorated oxidative stress in mitochondrial via the SIRT3/SOD2 signaling pathway, thereby promoting osteogenesis, improving bone mass around the prostheses, and increasing initial stability. Thus, melatonin might be a suitable candidate to decrease the rate of implant failure and lengthen the lifespan of prostheses after total joint arthroplasty.

Intervertebral disc (IVD) degeneration (IDD) is a major cause of low back pain. The pathogenesis of IDD is associated with the disturbance of reactive oxygen species (ROS) equilibrium, inflammation, and matrix loss. Aspirin is a nonsteroidal anti-inflammatory drug that effectively inhibits inflammation and oxidative stress and has been widely used for the treatment of back pain. Therefore, we hypothesize that aspirin reverses the IDD process via antioxidative and anti-inflammatory effects on the AMPK signaling pathway. In vitro, aspirin diminished cellular oxygen free radicals (ROS, nitric oxide (NO)) and inflammatory cytokines (interleukin- (IL-) 1β and IL-6 and tumor necrosis factor alpha (TNF-α)) induced by lipopolysaccharides (LPS) in nucleus pulposus cells (NPCs). We found that aspirin preserved the extracellular matrix (ECM) content of collagen type II (COL2) and aggrecan while inhibiting the expression of matrix-degenerating enzymes, including matrix metalloproteinase 3 and 13 (MMP-3 and MMP-13) and A disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4, ADAMTS-5). Aspirin significantly promoted the ratios of p-AMPK to AMPK and p-ACC to ACC expression in NPCs. Furthermore, pretreatment with the AMPK inhibitor compound C abrogated the antioxidant effects of aspirin. In vivo, an IDD model was established in Sprague-Dawley rats via percutaneous disc puncture with the 20-gauge needle on levels 8-9 and 9-10 of the coccygeal vertebrae. Imaging assessment showed that after aspirin treatment, improvements in disc height index (DHI) ranged from 1.22-fold to 1.54-fold and nucleus pulposus signal strength improved from 1.26-fold to 1.33-fold. Histological analysis showed that aspirin treatment prevented the loss of COL2 and decreased MMP-3 and MMP-13, inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), IL-1β, and TNF-α expression in the IVD tissues. These results suggest that treatment with aspirin could reverse the IDD process via the AMPK signaling pathway, which provides new insights into the potential clinical applications of aspirin, particularly for IDD treatment.

No abstract

Mesenchymal stem cells (MSCs) hold great potential to treat tissue damage based on their multipotent property, and are also considered as suitable cell resources to create tissue-engineered grafts for tendon repair. However, the clinical application of MSCs is still limited by the lack of efficient methods to induce tenogenic differentiation. In this study, by performing the experiments in transwell system, we found that paracrine factors from tenocytes could induce MSCs to undergo the tenogenic differentiation. We further verified that tenocytes could secrete exosomes and these tenocyte-derived exosomes efficiently initiated the tenogenic differentiation of MSCs. Finally, we revealed that the TGF-b existing in tenocyte-derived exosomes mediated the process, as the inhibition of TGF-b signaling abolished the effects of tenocyte-derived exosomes on MSCs. By investigating the effects of tenocytes on MSCs, we found that tenocytes-derived exosomes can induce tenogenic differentiation of MSCs in a TGF-b dependent manner. These studies provided critical information about the multipotency of MSCs and suggested potential strategies for clinical translation.