The journal retracts the article "FBXW7 Acts as an Independent Prognostic Marker and Inhibits Tumor Growth in Human Osteosarcoma" [...].

Discogenic low back pain (DLBP) is a multifactorial disease and associated with intervertebral disc degeneration. Calcitonin gene-related protein (CGRP) plays a critical role in pain processing, while the role in DLBP remains unclear. This study aims to investigate the anti-nociceptive role and related mechanisms of CGRP in DLBP. Here we established the DLBP rat and validated the model using histology and radiography. Minocycline, a microglial inhibitor, and CGRP were intrathecally injected and the behavioral test was performed to determine hyperalgesia. Further, BV2 microglial cells and microglial activation agent lipopolysaccharide (LPS) were employed for the in vitro experiment. We observed obvious lumbar intervertebral disc degeneration and hyperalgesia at 12 weeks postoperation in DLBP group, with significantly activated microglia in the spinal cord. CGRP treatment significantly inhibited the upregulation of proinflammatory cytokines and NLRP3/caspase-1 expression induced by LPS in BV2 cells, whereas treatment with CGRP alone had little effect on BV2 cells. The intrathecal injection of CGRP into DLBP rats relieved mechanical and thermal hyperalgesia, reverted the microglial activation and decreased the expression of NLRP3/caspase-1, similar to the effects produced by minocycline. Our results provide evidence that microglial activation in the spinal cord play a key role in hyperalgesia in DLBP rats. CGRP alleviates DLBP induced hyperalgesia and inhibits microglial activation in the spinal cord. Regulation of CGRP and microglial activation may provide a new strategy for ameliorating DLBP.

Significance of endogenous mineralization in bone reconstruction is paramount, as it facilitates the accumulation of calcium ions for bone tissue deposition. However, conventional 3D‐printed scaffolds lack the capacity for calcium ion enrichment and mineralization, coupled with their low bone inductive activity. Inspired from the development of natural plant seeds, a biomimetic 3D printing scaffold is developed by implanting photosensitive black phosphorus “bone seeds” (BS), guiding a sequential process mirroring rooting (osteoblast recruitment), sprouting (fibrous callus mineralization), flowering (osseous callus formation), and fruiting (callus plasticity). BS were trapped onto porous 3D polycaprolactone (PCL) scaffolds with aminated surfaces via electrostatic interactions between phosphates and amino groups, creating the PCL‐BS scaffold that can actively capture calcium ions for accelerating the endogenous regeneration of critical bone defects. In vitro and in vivo experiments show that the PCL‐BS scaffold has good biocompatibility and strong osteogenic ability for rapid new bone regeneration under near‐infrared (NIR) stimulation. In addition, whole transcriptome sequencing analysis is performed to reveal the transcriptomic mechanism of BS involved in signal transduction and network regulation during bone regeneration. This NIR light‐regulated biomimetic BS inspired by seed planting, introduces a pioneering concept in the design of 3D printing bone repair scaffolds.

Postmenopausal osteoporosis, a metabolic bone disease associated with aging that affects bones throughout the body, is emerging as an urgent public health concern and imposes a substantial healthcare burden on society. The clinical application of bisphosphonate, the primary treatment for osteoporosis, is limited owing to the drug’s severe complications. Herein, we investigate the synthesis and utilization of strontium-doped mesoporous bioactive glass loaded with alendronate (ALN@Sr-MBG) as a novel therapeutic agent for osteoporosis, to explore its potential as an alternative to alendronate (ALN). Strontium-doped mesoporous bioactive glass (Sr-MBG) was synthesized using the sol–gel method, while ALN@Sr-MBG was obtained via incorporating Sr-MBG into an alendronate saturated solution. The bioactivities of ALN@Sr-MBG, including biotoxicity, inflammation inhibition, and anti-osteoclast differentiation, were investigated in vitro using CCK-8, flow cytometry, tartrate-resistant acid phosphatase (TRAP) staining, and RT-PCR assays. Animal models were established by surgically removing the ovaries from non-pregnant female C57/BL mice, followed by weekly intraperitoneal injections of ALN@Sr-MBG, ALN, or excipients. After 8 weeks, the mice femurs were extracted and analyzed through micro-CT scanning and hematoxylin-eosi, osteoblastic, and osteogenic staining. These in vitro findings demonstrate that ALN@Sr-MBG displays enhanced biological efficacy compared to ALN in terms of inflammation inhibition, osteogenesis promotion, and osteoclastogenesis inhibition. Furthermore, micro-CT analysis revealed that ALN@Sr-MBG significantly augments bone mineral density (BMD), bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), while reducing trabecular separation (Tb.Sp) and the structural model index (SMI) in mice with ovariectomy-induced osteoporosis. The osteoblast and osteogenic staining results indicate the enhanced bioactivities of ALN@Sr-MBG in promoting bone formation and inhibiting bone resorption compared to ALN. In vitro and in vivo assessments further confirmed that ALN@Sr-MBG exhibits superior anti-osteoporotic bioactivity compared to ALN. This study’s findings confirm the potential of ALN@Sr-MBG as a novel alternative therapy to ALN and a drug candidate for the treatment of osteoporosis.

Osteoporosis (OP) is a chronic metabolic bone disease characterized by diminished bone mass, decreased bone strength, deterioration of bone microarchitecture, and increased bone fragility with fracture risk. The aging population has made OP a public health problem that has serious effects on individuals, families, and society as a whole. It is urgent that new strategies that are safe, effective, and inexpensive for the treatment of OP should be developed. Increasing evidence has suggested that the gut microbiota (GM) is inextricably linked to bone homeostasis through cross-talk between host and microbiota. During the development of OP, GM perturbations can initiate and reinforce the disruption of bone remodeling balance. In this review, we first review the current knowledge of how the GM affects bone metabolism, and conclude that GM changes bone metabolism and participates in the formation of OP by affecting intestinal barrier, host metabolites, immune system and endocrine system. Then, we discuss that probiotics are expected to be a potential oral therapeutic strategy for OP, but there are limitations. Furthermore, we discuss how bioactive functional materials for providing probiotics to the gut can be constructed based on the chemical barrier, biological barrier, immune barrier, and mechanical barrier in the gut. This review is anticipated to stimulate further innovative thinking focusing on the intestinal barrier as a key target for delivery of probiotics and treatment of OP.

Postmenopausal osteoporosis (PMO) is often accompanied by neuroendocrine changes in the hypothalamus, which closely associates with the microbial diversity, community composition, and intestinal metabolites of gut microbiota (GM). With the emerging role of GM in bone metabolism, a potential neuroendocrine signal neuropeptide Y (NPY) mediated brain-gut-bone axis has come to light. Herein, it is reported that exogenous overexpression of NPY reduced bone formation, damaged bone microstructure, and up-regulated the expressions of pyroptosis-related proteins in subchondral cancellous bone in ovariectomized (OVX) rats, but Y1 receptor antagonist (Y1Ra) reversed these changes. In addition, it is found that exogenous overexpression of NPY aggravated colonic inflammation, impaired intestinal barrier integrity, enhanced intestinal permeability, and increased serum lipopolysaccharide (LPS) in OVX rats, and Y1Ra also reversed these changes. Most importantly, NPY and Y1Ra modulated the microbial diversity and changed the community composition of GM in OVX rats, and thereby affecting the metabolites of GM (e.g., LPS) entering the blood circulation. Moreover, fecal microbiota transplantation further testified the effect of NPY-mediated GM changes on bone. In vitro, LPS induced pyroptosis, reduced viability, and inhibited differentiation of osteoblasts. The study demonstrated the existence of NPY-mediated brain-gut-bone axis and it might be a novel emerging target to treat PMO.

Discogenic low back pain (DLBP) is a multifactorial disease, associated with intervertebral disc degeneration. Calcitonin gene-related protein (CGRP) plays a critical role in pain processing, while the role in DLBP remains unclear. This study aims to investigate the anti-nociceptive role and related mechanisms of CGRP in DLBP. Here we established the DLBP rat and validated the model using histology and radiography. CGRP and minocycline were intrathecally injected respectively and the behavioral test was performed to determine hyperalgesia. Further, BV2 microglial cells and microglial activation agent lipopolysaccharide (LPS) were employed for the in vitro experiment. We observed obvious lumbar intervertebral disc degeneration and hyperalgesia at 12 weeks postoperation in DLBP group, with significantly activated microglia in the spinal cord. CGRP treatment significantly inhibited the upregulation of proinflammatory cytokines and NLRP3/caspase-1 expression induced by LPS in BV2 cells, whereas treatment with CGRP alone had little effect on BV2 cells. The intrathecal injection of CGRP into DLBP rats relieved mechanical and thermal hyperalgesia, reverted the microglial activation and decreased the expression of NLRP3/caspase-1, similar to the effects produced by minocycline. Our results provide evidence that microglial activation in the spinal cord play a key role in hyperalgesia in DLBP rats. CGRP effectively alleviates hyperalgesia and inhibits microglial activation in the spinal cord. Regulation of CGRP and microglial activation may provide a new strategy for ameliorating for DLBP.

The neuropeptide Y(NPY) mediates bone metabolism and the degradation of cartilage in the peripheral nervous system. However, its role in the intervertebral disc degeneration (IDD) is less clear and warrant further study. The process of IDD has always been accompanied by inflammatory response and pyroptosis of nucleus pulposus cells (NPCs). The aim of this study was to investigate the relationship between NPY, Y1R, Y2R and pyroptosis in aging and degenerative discs and the direct effect of NPY on NPCs. First, we have assessed NPY, Y1R, Y2R and the expression of pyroptosis related protein in the immature (6 weeks), mature (16 weeks), aged (54 weeks), and degenerated discs. As part of our studies, we also have evaluated pyroptotic changes in the NPCs, induced by exposure to NPY. Our results suggested that compared with natural aging discs, the degenerative discs showed the high expression of NPY, Y1R and Y2R. Correlation analysis showed that the level of NPY and Y1R in degenerative discs were positively correlated with GSDMD, whereas there was no significant correlation between Y2R and GSDMD. In vitro, NPY treatment stimulated the activation of caspase-1-dependent pyroptosis of NPCs. However, Y1R antagonist inhibited NPY-induced pyroptosis of NPCs. Western blot confirmed that Y1R antagonist decreased the level of cleaved.GSDMD and caspase-1 in NPCs. In conclusion, our results indicated that compared with natural aging discs, the degenerated discs showed the high expression of NPY, Y1R and Y2R. NPY-Y1R involve the IDD development by the regulation of pyroptosis in the NPCs. Regulating the function of NPY may be a promising strategy for IDD treatment.

BackgroundBibliometric analysis was designed to investigate a systematic understanding of developments in exercise and osteoporosis research over the past 20 years. MethodsRelevant publications from the Web of Science Core Collection were downloaded on April 26, 2022. CiteSpace, VOSviewer, and the online bibliometric analysis platform were used to conduct this scientometric study. ResultsA total of 5518 publications were in 1202 academic journals with 137405 co-cited references in by 5637 institutions from 98 countries/regions. The country leading the research was the USA. The University of Melbourne was the most active institution. Osteoporosis International was the most productive journal concerning exercise and osteoporosis research. According to the burst references, "low-level vibration," "high-frequency" and "resistance exercise" have been recognized as the hotspots research in the domain. The keywords co-occurrence analysis identified "skeletal muscle," "sarcopenia" and "mesenchymal stem cell" as the important future research directions. ConclusionThis study was the first comprehensive metrological and statistical analysis of exercise and osteoporosis research over the past 20 years. Our findings would provide guidance to understand the research frontiers and hot directions in the near future.

椎间盘退变是退变性脊柱疾病的关键病因和病理基础,探讨椎间盘退变的病理机制对退变性脊柱疾病的防治具有重要意义.近年来,越来越多的研究表明神经肽Y(neuropeptide Y,NPY)在椎间盘退变的病理机制中发挥重要作用.本文就NPY参与椎间盘退变发病机制的研究进展进行综述,以期为退变性脊柱疾病的防治提供新参考.

Lumbar spinal stenosis (LSS) is a condition wherein patients exhibit age-related fibrosis, elastin-to-collagen ratio reductions, and ligamentum flavum hypertrophy. This study was designed to assess the relationship between SIRT6 and telomerase activity in hypertrophic ligamentum flavum (LFH) cells from LSS patients. We observed significant reductions in SIRT6, TPP1, and POT1 protein levels as well as increases in telomerase reverse transcriptase (TERT) levels and telomerase activity in LFH tissues relative to non- hypertrophic ligamentum flavum (LFN) tissues. When SIRT6 was overexpressed in these LFH cells, this was associated with significant increases in telomerase activity and a significant reduction in fibrosis-related protein expression. These effects were reversed, however, when telomerase activity was inactivated by hTERT knockdown in these same cells. SIRT6 overexpression was further found to reduce the frequency of senescence-associated β-galactosidase (SA-β-Gal)-positive LFH cells and to decrease p16, MMP3, and L1 mRNA levels and telomere dysfunction-induced foci (TIFs) in LFH cells. In contrast, hTERT knockdown-induced telomerase inactivation eliminated these SIRT6-dependent effects. Overall, our results indicate that SIRT6 functions as a key protective factor that prevents cellular senescence and telomere dysfunction in ligamentum flavum cells, with this effect being at least partially attributable to SIRT6-dependent telomerase activation.

目的 减轻患者下肢换药时带来的疼痛不适,减少因换药时人工抬高患侧肢体引起的骨折移位及人力所需的额外工时,增加患者换药时的舒适度.方法 选择我院创伤骨科收治的卧床下肢骨折换药患者90例为研究对象,随机分为观察组和对照组,各45例,观察组应用自行设计骨科换药支架,对照组使用常规换药方法.采用自拟舒适度自评量表和视觉模拟评分法(VAS)评价患者使用效果.对骨科47名医护人员采用自拟换药支架评价量表,了解其使用感受.结果 观察组患者换药时舒适性评价明显优于对照组,2组比较差异有统计学意义(P＜0.05).观察组患者VAS评分明显低于对照组,差异有统计学意义(P＜0.05).28名医生和19名护士对换药支架的自评总分为(98.61±1.34)分和(98.47±1.17)分,对使用换药支架满意度较高.结论 骨科卧床的应用可缩短换药时间,提高患者舒适度,减轻疼痛,降低医护机械性损伤的可能,在一定程度上减轻换药负担.

Osteoporosis is a common metabolic bone disorder in the elderly population. The accumulation of bone microdamage is a critical factor of osteoporotic fracture. Neuropeptide Y (NPY) has been reported to regulated bone metabolism through Y1 receptor (Y1R). In this study the effects and mechanisms of Y1R antagonist on prevention for osteoporosis were characterized. In the clinical experiment, compared with osteoarthritis (OA), osteoporosis (OP) showed significant osteoporotic bone microstructure and accumulation of bone microdamage. NPY and Y1R immunoreactivity in bone were stronger in OP group, and were both correlated with bone volume fraction (BV/TV). In vivo experiment, Y1R antagonist significantly improved osteoporotic microstructure in the ovariectomized (OVX) rats. And Y1R antagonist promoted RUNX2, OPG and inhibit RANKL, MMP9 in bone marrow. In vitro cell culture experiment, NPY inhibited osteogenesis, elevated RANKL/OPG ratio and downregulated the expression of cAMP, p-PKAs and p-CREB in BMSCs, treated with Y1R antagonist or 8-Bromo-cAMP could inhibit the effects of NPY. Together, Y1R antagonist improved the bone microstructure and reduced bone microdamage in OVX rats. NPY-Y1R could inhibit osteoblast differentiation of BMSCs via cAMP/PKA/CREB pathway. Our findings highlight the regulation of NPY-Y1R in bone metabolism as a potential therapy strategy for the prevention of osteoporosis and osteoporotic fracture.

A plethora of evidence has suggested that gut microbiota is involved in the occurrence and development of postmenopausal osteoporosis (PMO). It has been suggested that neuropeptide Y (NPY) modulates the bone metabolism through Y1 receptor (Y1R), and might be associated with gut microbiota. The present study aims to evaluate the anti-osteoporotic effects of Y1R antagonist and to investigate the potential mechanism by which Y1R antagonist regulates gut microbiota. In this study, eighteen female rats were randomly divided into three groups: the sham surgery (SHAM) group, the ovariectomized (OVX) group, and OVX+BIBO3304 group. After 6 weeks following surgery, Y1R antagonist BIBO3304 was administered to the rats in OVX+BIBO3304 group for 7 days. The bone microstructure and serum biochemical parameters were measured at 12 weeks after operation. The differences in the gut microbiota were analyzed by 16S rDNA gene sequencing. Heat-map and Spearman’s correlation analyses were constructed to investigate the correlations between microbiota and bone metabolism-related parameters. The results indicated that OVX+BIBO3304 group showed significantly higher BMD, BV/TV, Tb.Th, Tb.N, Conn.D, and serum Ca2+ level than those in OVX group. Additionally, Y1R antagonist changed the gut microbiota composition with lower Firmicutes/Bacteroidetes ratio and higher proportions of some probiotics, including Lactobacillus. The correlation analysis showed that the changes of gut microbiota were closely associated with bone microstructure and serum Ca2+ levels. Our results suggested that Y1R antagonist played an anti-osteoporotic effect and regulated gut microbiota in OVX rats, indicating the potential to utilize Y1R antagonist as a novel treatment for PMO.

Recently, aberrant expression of miR-876-5p has been reported to participate in the progression of several human cancers. However, the expression and function of miR-876-5p in osteosarcoma (OS) are still unknown. Here, we found that the expression of miR-876-5p was significantly down-regulated in OS tissues compared to para-cancerous tissues. Clinical association analysis indicated that underexpression of miR-876-5p was positively correlated with advanced clinical stage and poor differentiation. More importantly, OS patients with low miR-876-5p level had a significant shorter overall survival compared to miR-876-5p high-expressing patients. In addition, gain- and loss-of-function experiments demonstrated that miR-876-5p restoration suppressed whereas miR-876-5p knockdown promoted cell proliferation, migration and invasion in both U2OS and MG63 cells. In vivo studies revealed that miR-876-5p overexpression inhibited tumour growth of OS in mice. Mechanistically, miR-876-5p reduced c-Met abundance in OS cells and inversely correlated c-Met expression in OS tissues. Herein, c-Met was recognized as a direct target of miR-876-5p using luciferase reporter assay. Notably, c-Met restoration rescued miR-876-5p attenuated the proliferation, migration and invasion of OS cells. In conclusion, these findings indicate that miR-876-5p may be used as a potential therapeutic target and promising biomarker for the diagnosis and prognosis of OS.

目的:观察神经肽Y(neuropeptide Y,NPY)及Y1R、Y2R在椎间盘退变(intervertebral disc degeneration,IDD)组和假手术(sham operation,SHAM)组大鼠椎间盘(intervertebral disc,IVD)和背根神经节(dorsal root ganglion,DRG)表达的差异,以及与大鼠机械缩足阈值(mechanical withdrawal threshold,MWT)和热缩足反射潜伏期(thermal withdrawal latency,TWL)的相关关系,探讨NPY及受体与椎间盘源性腰痛的关系.方法:选择6月龄无特定病原体(specific pathogen free,SPF)级雌性未孕SD大鼠12只,随机分为椎间盘退变组和假手术组(n=6),前者采用动静力失衡大鼠椎间盘退变模型,后者做假手术处理,造模后12周通过MRI和X线评估椎间盘退变模型建立是否成功并测量2组大鼠MWT及TWL,使用免疫组织化学法检测2组大鼠IVD和DRG中NPY及受体的表达,分析其平均光密度(mean optical density,MOD)值与疼痛行为学之间的相关性.结果:①疼痛检测发现,术后12周IDD组大鼠MWT较SHAM组大鼠明显降低[(9.44±2.91)g vs.(17.99±4.40)g,P=0.002],TWL明显降低[(9.17±0.39)s vs.(13.53±1.69)s,P=-0.002].②免疫组织化学法检测显示,与SHAM组相比,IDD组大鼠IVD和DRG中NPY的表达明显升高[IVD:[(0.15±0.03) vs.(0.11±0.02),P=0.021;DRG:(0.23±0.04) vs.(0.17±0.04),P=0.018],Y1R表达明显降低[IVD:(0.10±0.02) vs.(0.13±0.01),P=0.009;DRG:(0.05±0.01)vs.(0.08±0.01),P=0.000],2组大鼠IVD和DRG中Y2R的表达差异均无统计学意义.③Pearson相关性分析表明,2组大鼠IVD和DRG中NPY的MOD值与MWT之间成负相关关系(r=-0.605,P=0.037;r=-0.617,P=0.033);2组大鼠IVD和DRG中Y1R的MOD值与MWT之间成正相关关系(r=0.696,P=0.012;r=0.735,P=0.006).2组大鼠IVD和DRG中NPY的MOD值与TWL之间成负相关关系(r=-0.603,P=0.038;r=-0.708,P=0.010);2组大鼠IVD和DRG中Y1R的MOD值与TWL之间成正相关关系(r=0.624,P=0.030;r=0.834,P=0.001).结论:在腰椎动静力失衡大鼠模型中,NPY可能通过外周Y1R参与椎间盘源性腰痛的发生发展,但其具体机制有待进一步研究.

OBJECTIVES:Postmenopausal osteoporosis (PMO) is a metabolic skeletal disorder with impaired bone density and bone quality in postmenopausal women. The aim of the present study was to investigate the correlation between neuropeptides, bone microstructure and pain threshold in ovariectomized (OVX) rats. METHODS:Female rats were randomly divided into the ovariectomized (OVX) group and the sham surgery (SHAM) group. Bone microstructure and immunocytochemistry for substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) in tibial and DRG were performed. Pain threshold was assessed at post-operative 11 weeks. Pearson correlation coefficients were calculated between neuropeptides, bone microstructure and pain threshold. RESULTS:Significant decreases in bone volume fraction (BV/TV) and trabecular number (Tb. N) but significant increases in trabecular spacing (Tb.Sp) were showed in OVX group. Mechanical pain threshold (MPT) in OVX group was significantly decreased. The MOD values for SP, CGRP and VIP of tibial in OVX group were significantly lower, whereas NPY, NPY1R and NPY2R were significantly higher. And SP, CGRP, VIP, NPY and NPY2R of DRG were significantly increased in OVX group, while NPY1R was significantly decreased. Correlation analysis showed that NPY, Y1R and Y2R in bone were negatively correlated with BV/TV. MPT was negatively correlated with NPY and Y2R in DRG, and positively correlated with Y1R in DRG. CONCLUSIONS:Our results suggested that SP, CGRP, VIP and NPY were involved in the osteoporotic bone microstructure and mechanical hypersensitivity in OVX rats, indicating the potential to utilize neuropeptides as novel therapeutic targets for PMO.

This study aimed to evaluate the bioactivity and cytocompatibility of mesoporous bioactive glass. The structure and components of mesoporous bioactive glass 80S MBG were characterized. Mouse osteoblasts were isolated and treated with 80S MBG. The viability and alkaline phosphatase activity of osteoblasts were evaluated. Hydroxyapatite was at the surface of 80S MBG after 4 h, and Ca, P and Si concentration rapidly reached the peak within 1-4 h. pH change was very slight. Mouse osteoblasts seeded in the flask could adhere to the surface and maintain normal morphology. The extract of 80S MBG promoted the proliferation of osteoblasts at lower concentrations, and promoted the differentiation of osteoblasts at higher concentrations. The toxicity gradation of 80S MBG was 0-1. In conclusion, 80S MBG has higher biological activity and good cell compatibility in vitro. The influence for body fluid microenvironment is mild. 80S MBG could be used as a substitute material or scaffold in bone tissue engineering.

Background. Inflammation might play a crucial role in the pathogenesis of osteoarthritis (OA). Interleukin-34 (IL-34) is a well-known proinflammatory cytokine. Objective. The objective of this study was to detect IL-34 levels in serum and synovial fluid (SF) of patients with OA and to investigate their correlation with radiographic and symptomatic severity. Methods. One hundred and eighty-two OA patients and 69 controls were recruited. IL-34 levels were measured by enzyme-linked immunosorbent assay (ELISA). Radiographic and symptomatic severity of OA was reflected by Kellgren-Lawrence (KL) grades and Western Ontario McMaster University Osteoarthritis Index (WOMAC) scores, respectively. Results. SF IL-34 levels were independently associated with the KL grade (B=0.273, 95% CI: 0.150–0.395; P<0.001). SF IL-34 levels were significantly correlated with WOMAC scores (r=0.265, 95% CI: 0.123–0.399; P<0.001). The correlation between SF IL-34 levels and WOMAC scores was still significant after adjusting for confounding factors (B=0.020, 95% CI: 0.001–0.038; P=0.035) in OA patients. Conclusions. We found that IL-34 levels in SF were significantly associated with the radiographic and symptomatic severity of knee OA.