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Introduction: Accelerated imbalance between bone formation and bone resorption is associated with bone loss in postmenopausal osteoporosis. Studies have shown that this loss is accompanied by an increase in bone marrow adiposity. Melatonin was shown to improve impaired bone formation capacity of bone marrow-derived mesenchymal stem cells from ovariectomized rats (OVX-BMMSCs)., Objectives: To investigate whether the anti-osteoporosis effect of melatonin involves regulation of the equilibrium between osteogenic and adipogenic differentiation of osteoporotic BMMSCs., Methods: To induce osteoporosis, female Sprague-Dawley rats received ovariectomy (OVX). Primary BMMSCs were isolated from tibiae and femurs of OVX and sham-op rats and were induced towards osteogenic or adipogenic differentiation. Matrix mineralization was determined by Alizarin Red S (ARS) and lipid formation was evaluated by Oil Red O. OVX rats were injected with melatonin through the tail vein. Bone microarchitecture was determined using micro computed tomography and marrow adiposity were examined by histology staining., Results: OVX-BMMSCs exhibited a compromised osteogenic potential and an enhanced lineage differentiation towards adipocytes. In vitro melatonin improved osteogenic differentiation of OVX-BMMSCs and promoted matrix mineralization by enhancing the expression of transcription factor RUNX2 in a dose-dependent manner. Moreover, melatonin significantly inhibited lipid formation and suppressed OVX-BMMSCs adipogenesis by down-regulating peroxisome proliferator-activated receptor γ (PPARγ). Intravenous injection of melatonin prevented bone mass reduction and bone architecture destruction in ovariectomized rats. Importantly, there was a significant inhibition of adipose tissue formation in the bone marrow. Mechanistic investigations revealed that SIRT1 was involved in melatonin-mediated determination of stem cell fate. Inhibition of SIRT1 abolished the protective effects of melatonin on bone formation by inducing BMMSCs towards adipocyte differentiation., Conclusions: Melatonin reversed the differentiation switch of OVX-BMMSCs from osteogenesis to adipogenesis by activating the SIRT1 signaling pathway. Restoration of stem cell lineage commitment by melatonin prevented marrow adipose tissue over-accumulation and protected from bone loss in postmenopausal osteoporosis., The Translational Potential of This Article: Determination of stem cell fate towards osteoblasts or adipocytes plays a pivotal role in regulating bone metabolism. This study demonstrates the protective effect of melatonin on bone mass in estrogen-deficient rats by suppressing adipose tissue accumulation in the bone marrow. Melatonin may serve as a promising candidate for the treatment of osteoporosis in clinics., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Objective: To compare the clinical efficacy, complications, and reoperation rates among three major treatments for lumbar spinal stenosis (LSS): decompression, fusion, and interspinous process device (IPD), using a Bayesian network meta-analysis., Materials and Methods: Databases including Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were used for the literature search. Randomized Controlled Trials (RCTs) with three treatment methods were reviewed and included in the study. R software (version 3.6.0), Stata (version 14.0), and Review Manager (version 5.3) were used to perform data analysis., Results: A total of 10 RCTs involving 1254 patients were enrolled in the present study and each study met an acceptable quality according to our quality assessment described later. In direct comparison, IPD exhibited a higher incidence of reoperation than fusion (OR ​= ​2.93, CI: 1.07-8.02). In indirect comparison, the rank of VAS leg (from best to worst) was as follows: IPD (64%) ​> ​decompression (25%) ​> ​fusion (11%), and the rank of ODI (from best to worst) was: IPD (84%) ​> ​fusion (13%) ​> ​decompression (4%). IPD had the lowest incidence of complications; the rank of complications (from best to worst) was: IPD (60%) ​> ​decompression (27%) ​> ​fusion (14%). However, for the rank of reoperation, fusion showed the best results (from best to worst): fusion (79%) ​> ​decompression (20%) ​> ​IPD (1%). Consistency tests at global and local level showed satisfactory results and heterogeneity tests using loop text indicated a favorable stability., Conclusion: The present study preliminarily indicates that non-fusion methods including decompression and IPD are optimal choices for treating LSS, which achieves favorable clinical outcomes. IPD exhibits a low incidence of complications, but its high rate of reoperation should be treated with caution., The Translational Potential of This Article: For the treatment of LSS, several procedures including decompression, fusion, and IPD have been reported. However, each method has its own advantages and disadvantages. To date, the golden standard treatment for LSS is still controversial. In this network meta-analysis, our results demonstrate that both decompression and IPD obtain satisfactory clinical effects for LSS. IPD is accompanied with a low incidence of complications, however, its high rate of reoperation should be acknowledged with discretion., Competing Interests: The authors have no conflicts of interest to disclose in relation to this article., (© 2020 The Authors.)

Background: Tissue engineering of the annulus fibrosus (AF) shows promise as a treatment for patients with degenerative disc disease (DDD). However, it remains challenging due to the intrinsic heterogeneity of AF tissue. Fabrication of scaffolds recapitulating the specific cellular, componential, and microstructural features of AF, therefore, is critical to successful AF tissue regeneration., Methods: Poly-L-lactic acid (PLLA) fibrous scaffolds with various fiber diameters and orientation were prepared to mimic the microstructural characteristics of AF tissue using electrospinning technique. AF-derived stem cells (AFSCs) were cultured on the PLLA fibrous scaffolds for 7 days., Results: The morphology of AFSCs significantly varied when cultured on the scaffolds with various fiber diameters and orientation. AFSCs were nearly round on scaffolds with small fibers. However, they became spindle-shaped on scaffolds with large fibers. Meanwhile, upregulated expression of collagen-I gene happened in cells cultured on scaffolds with large fibers, while enhanced expression of collagen-II and aggrecan genes was seen on scaffolds with small fibers. The production of related proteins also showed similar trends. Further, culturing AFSCs on a heterogeneous scaffold by overlaying membranes with different fiber sizes led to the formation of a hierarchical structure approximating native AF tissue., Conclusion: Findings from this study demonstrate that fibrous scaffolds with different fiber sizes effectively promoted the differentiation of AFSCs into specific cells similar to the types of cells at various AF zones. It also provides a valuable reference for regulation of cell differentiation and fabrication of engineered tissues with complex hierarchical structures using the physical cues of scaffolds., The Translational Potential of This Article: Effective AF repair is an essential need for treating degenerative disc disease. Tissue engineering is a promising approach to achieving tissue regeneration and restoring normal functions of tissues. By mimicking the key structural features of native AF tissue, including fiber size and alignment, this study deciphered the effect of scaffold materials on the cell differentiation and extracellular matrix deposition, which provides a solid basis for designing new strategies toward more effective AF repair and regeneration., Competing Interests: The authors have no conflicts of interest to disclose in relation to this article., (© 2020 The Author(s).)

Background: The survival rate of osteosarcoma therapy still lags behind overall cancer therapies due to the intrinsic or acquired drug resistance. Developing novel drug delivery systems that may overcome drug resistance would greatly facilitate osteosarcoma therapy., Methods: Poly(ethylene glycol) (PEG)-sheddable reduction-sensitive polyurethane (SS-PU-SS-PEG) was synthesized using a disulfide-containing polycaprolactone diol as the hydrophobic block and a cystamine-functionalized PEG as the hydrophilic block. SS-PU-SS-PEG micelles were then prepared to load the anti-tumor drug Doxorubicin (DOX) in order to achieve triggered intracellular drug delivery to improve the efficacy of osteosarcoma therapy., Results: When DOX was used as a model drug, the drug-loaded SS-PU-SS-PEG micelles were about 82∼94 nm in diameter and exhibited good stability in phosphate buffer saline (PBS). The micelles could release about 80% DOX in a quantitative fashion within 5 hours under a reductive environment. The intracellular drug release of DOX-loaded SS-PU-SS-PEG micelles increased upon incubation with Saos-2 cells in vitro. The micelles had good biocompatibility. In vitro, DOX-loaded SS-PU-SS-PEG micelles showed significant antitumor activity toward Saos-2 cells, which was close to that of free DOX. In vivo, DOX-loaded SS-PU-SS-PEG micelles exhibited better antitumor activity than free DOX., Conclusion: Findings from this study suggest that the SS-PU-SS-PEG micelles could achieve well-controlled triggered drug release in a reduction environment and could therefore improve the antitumor efficacy of osteosarcoma therapies., Translation Potential of This Article: In this study we developed PEG-sheddable reduction-sensitive polyurethane micelles (SS-PU-SS-PEG), which were able to achieve well-controlled triggered release of anti-tumor drug Doxorubicin (DOX) in an intracellular reduction environment. DOX-loaded SS-PU-SS-PEG micelles markedly improved the antitumor efficacy in a Saos-2 cells-bearing xenograft tumor model. Therefore, such micelles might be used as a novel drug delivery system for osteosarcoma treatment., (© 2019 The Author(s).)