The potential remedy of melatonin on osteoarthritis.

Osteoarthritis (OA), the most common arthritis worldwide, is a degenerative joint disease characterized by progressive cartilage breakdown, subchondral remodeling, and synovial inflammation. Although conventional pharmaceutical therapies aimed to prevent further cartilage loss and joint dysfunction, there are no ideal strategies that target the pathogenesis of OA. Melatonin exhibits a variety of regulatory properties by binding to specific receptors and downstream molecules and exerts a myriad of receptor-independent actions via intracellular targets as a chondrocyte protector, an anti-inflammation modulator, and a free radical scavenger. Melatonin also modulates cartilage regeneration and degradation by directly/indirectly regulating the expression of main circadian clock genes, such as transcriptional activators [brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (Bmal) and circadian locomotor output cycles kaput (Clock)], transcriptional repressors [period circadian regulator (Per)1/2, cryptochrome (Cry)1/2, and Dec2], and nuclear hormone receptors [Rev-Erbs and retinoid acid-related orphan receptors (Rors)]. Owing to its effects on cartilage homeostasis, we propose a potential role for melatonin in the prevention and therapy of OA via the modulation of circadian clock genes, mitigation of chondrocyte apoptosis, anti-inflammatory activity, and scavenging of free radicals.

Different molecular weights of hyaluronan research in knee osteoarthritis: A state-of-the-art review.

Osteoarthritis (OA), the most common form of arthritis, is characterized by progressive cartilage destruction, concomitant adaptive osteogenesis, and loss of joint function. The progression of OA with aging is associated with a decrease in native hyaluronan (HA, hyaluronate or hyaluronic acid) with a high molecular weight (HMW) in synovial fluid and a subsequent increase in lower MW HA and fragments. As HMW HA possesses numerous biochemical and biological properties, we review new molecular insights into the potential of HA to modify OA processes. Different MWs in the formulation of products appear to have varying effects on knee OA (KOA) pain relief, improved function, and postponing surgery. In addition to the safety profile, more evidence indicates that intraarticular (IA) HA administration may be an effective option to treat KOA, with a particular emphasis on the use of HA with fewer injections of higher MW, including potential applications of HA of very HMW. We also analyzed published systemic reviews and meta-analyses of IA HA in treating KOA in order to discuss their conclusions and consensus statements. According to its MW, HA may offer a simple way to refine therapeutic information in selective KOA.

Curcumin and its Analogs and Carriers: Potential Therapeutic Strategies for Human Osteosarcoma.

Curcumin is a natural polyphenol phytochemical derived from turmeric with antioxidant, anti-inflammatory, and anticancer properties but is concerned about poor solubility in water, absorption, and metabolic stability. Potent metastatic osteosarcoma is the most common primary bone cancer in children, adolescents, and young adults. It is responsible for low survival rates because of its high rate of metastasis to the lungs. To improve poor bioavailability, numerous curcumin analogs were developed to possess anticancer characteristics through a variety of biological pathways involved in cytotoxicity, proliferation, autophagy, sensitizing chemotherapy, and metastases. This review provides an overview of their various pharmacological functions, molecular mechanisms, and therapeutic potential as a remedy for human osteosarcoma. To enhance therapeutic efficacy, several liposomal nanoparticles, nanocarriers, multifunctional micelles, and three-dimensional printed scaffolds have also been developed for the controlled delivery of curcumin targeting human osteosarcoma cells. Consequently, curcumin and several potential analogs and delivery formulations are optimistic candidates to improve the currently available strategy for human osteosarcoma. However, further insight into the mechanism of action of promising curcumin analogs and the development of carriers in clinical trials of osteosarcoma needs to be investigated to improve their overall potency and clinical utility, in particular the anti-metastatic effect.

Lipocalin-2 Inhibits Osteosarcoma Cell Metastasis by Suppressing MET Expression via the MEK-ERK Pathway.

Higher neutrophil-derived cytokine lipocalin-2 (LCN2) expression possesses a versatile role in a myriad of cancers, but little is known about the role of LCN2 on osteosarcoma metastasis. In this study, we demonstrated that higher LCN2 inhibited cellular motility, migration, and invasion of osteosarcoma cells. Moreover, using RNA sequencing technology, we found that LCN2 repressed MET gene expression in U2OS cells. Manipulation of LCN2 levels influenced the migratory potential of osteosarcoma cells as cellular migration was enhanced by transfecting with vectors containing a constitutively active LCN2 cDNA and recombinant human LCN2. Moreover, the phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 and ERK 1/2 was decreased by LCN2 knockdown. Furthermore, the use of ERK inhibitor (U0126) and activator (tBHQ) confirmed that the pharmaceutic inhibition of MEK-ERK augmented the LCN2-mediated MET suppression and migration of U2OS and HOS cells. Conclusively, LCN2 inhibits osteosarcoma cell metastasis by suppressing MET via the MEK-ERK pathway.

GO-Y078, a Curcumin Analog, Induces Both Apoptotic Pathways in Human Osteosarcoma Cells via Activation of JNK and p38 Signaling.

Osteosarcoma is the most common primary bone malignancy in teenagers and continues to confer a generally poor prognosis due to its highly metastatic potential. Poor solubility in water and instability of curcumin limits its bioavailability for use in the adjuvant situation to improve the prognosis and the long-term survival of patients with osteosarcoma. To further obtain information regarding the apoptosis induced by a new curcumin analog, GO-Y078, in human osteosarcoma cells, flow cytometric analysis, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. GO-Y078 dose-dependently decreased viabilities of human osteosarcoma U2OS, MG-63, 143B, and Saos-2 cells and induced sub-G1 fraction arrest and apoptosis in U2OS and 143B cells. In addition to the effector caspase 3 and poly adenosine diphosphate-ribose polymerase, GO-Y078 significantly activated both initiators of extrinsic caspase 8 and intrinsic caspase 9, whereas cellular inhibitors of apoptosis 1 (cIAP-1) and X-chromosome-linked IAP (XIAP) in U2OS and 143B cells were significantly repressed. Moreover, GO-Y078 increased phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2, and p38 in U2OS and 143B cells. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), GO-Y078's increases in cleaved caspases 8, 9, and 3 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Altogether, GO-Y078 simultaneously induces both apoptotic pathways and cell arrest in U2OS and 143B cells through activating JNK and p38 signaling and repressing IAPs. These findings contribute to a better understanding of the mechanisms responsible for GO-Y078's apoptotic effects on human osteosarcoma cells.

New insights into molecular and cellular mechanisms of zoledronate in human osteosarcoma.

Osteosarcoma is the most common primary malignant tumor of the skeleton in teenagers and young adults and continues to confer a generally poor prognosis in patients who do not respond to chemotherapy or who present with metastatic diseases at diagnosis. The nitrogen-containing zoledronate, the third generation bisphosphonate (BP), effectively inhibits osteoclastic bone resorption and is widely utilized in the treatment of metabolic and metastatic bone diseases nowadays. Owing to an acceptable safety profile and tolerability, zoledronate is the only BP currently approved for the prevention and treatment of skeletal relevant events in patients with metastatic bone lesions, especially bone metastases from advanced renal cell carcinoma and prostate cancer, and breast cancer, due to all solid malignancy. Moreover, zoledronate possesses diverse anti-osteosarcoma properties and may have potential to become an adjunctive treatment for high-grade osteosarcoma to enhance survival rates and to obliterate complications of the chemotherapy. Herein we highlighted the pharmacology of BPs and its underlying molecular mechanisms in osteoclasts and various cancer cells. We further provided the available literature on in vitro studies to illustrate the new insights into the intracellular molecular mechanisms of zoledronate in human osteosarcoma cell lines and in vivo animal models that led to the development and regulatory approval of zoledronate in patients with human osteosarcoma. This review also addresses clinical trials to focus on the efficacy of zoledronate on human osteosarcoma.