瘦素对骨关节炎影响的研究进展

瘦素(Leptin)是脂肪因子的一种,可以在骨关节炎(OA)患者的血浆、滑液、软骨中被检测到。OA是一种最常见的关节疾病,其可以发生于全身的多个关节,以骨质和滑膜组织新陈代谢的改变、关节软骨的破坏和由此引起的关节软骨的减少为特征。瘦素是一种由肥胖(0b)基因编码的一个小的非糖基化肽激素。最开始,瘦素仅仅被认为是一种脂肪细胞源性的小分子(16KD),在下丘脑中枢水平作为一个饱感因子介导食物摄入量减少,并增加能量的消耗。现在已经发现,瘦素在机体内可发挥多种生理作用,并与OA病情有关。本文通过对瘦素与OA、软骨、肥胖、生物标志物、脂联素等之间的联系做一综述,以了解瘦素与OA之间的联系,为OA的治疗方面的进一步研究提供帮助。     

Simultaneous bilateral posteromedial tibial epiphysis stress fractures in a healthy young man: A case report

We present a compelling case of simultaneous, bilateral tibial stress fractures occurring in a unique epiphyseal and posterior location, with unclear aetiology. An overweight, Caucasian male in his late 20s developed synchronous bilateral medial knee pain following an intense 10-day training regimen. His radiographies were normal, but MRI revealed almost identical bilateral stress fracture lines in the posteromedial tibial epiphyses. Bone mineral densitometry and a full metabolic and hormonal panel were performed to further investigate potential underlying metabolic bone disease. He was found to have normal bone mineral densitometry and low Vitamin D serum values. Symptomatology greatly improved with activity modification. There were no further complaints and complications at 12 months’ follow-up. Diagnosis can be challenging and the treating physician should be acquainted with the basic science of stress fractures and main discriminating clinical, biochemical and radiological characteristics from insufficiency fractures, to avoid pitfalls in treatment decision.     

Pharmacological treatment with diacerein combined with mechanical stimulation affects the expression of growth factors in human chondrocytes

BackgroundOsteoarthritis (OA) as the main chronic joint disease arises from a disturbed balance between anabolic and catabolic processes leading to destructions of articular cartilage of the joints. While mechanical stress can be disastrous for the metabolism of chondrocytes, mechanical stimulation at the physiological level is known to improve cell function. The disease modifying OA drug (DMOAD) diacerein functions as a slowly-acting drug in OA by exhibiting anti-inflammatory, anti-catabolic, and pro-anabolic properties on cartilage. Combining these two treatment options revealed positive effects on OA-chondrocytes.MethodsCells were grown on flexible silicone membranes and mechanically stimulated by cyclic tensile loading. After seven days in the presence or absence of diacerein, inflammation markers and growth factors were analyzed using quantitative real-time PCR and enzyme linked immune assays. The influence of conditioned medium was tested on cell proliferation and cell migration.ResultsTensile strain and diacerein treatment reduced interleukin-6 (IL-6) expression, whereas cyclooxygenase-2 (COX2) expression was increased only by mechanical stimulation. The basic fibroblast growth factor (bFGF) was down regulated by the combined treatment modalities, whereas prostaglandin E2 (PGE2) synthesis was reduced only under OA conditions. The expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor A (VEGF-A) was down-regulated by both.ConclusionsFrom our study we conclude that moderate mechanical stimulation appears beneficial for the fate of the cell and improves the pharmacological effect of diacerein based on cross-talks between different initiated pathways.General significanceCombining two different treatment options broadens the perspective to treat OA and improves chondrocytes metabolism.     

Kinematic evaluation of cruciate-retaining total knee replacement patients during level walking: A comparison with the displacement-controlled ISO standard

Differences between wear-scar features of simulator-tested and retrieved tibial total knee replacement (TKR) liners have been reported. This disagreement may result from differences between in vivo kinematic profiles and those defined by the International Organization for Standardization (ISO). The purpose of this study was to determine the knee kinematics of a TKR subject group during level walking and compare them with the motion profiles defined by the ISO standard for a displacement-controlled knee wear testing simulator. Twenty-nine patients with a posterior cruciate ligament-retaining TKR design were gait tested using the point cluster technique to obtain flexion–extension (FE) rotation, anterior–posterior (AP) translation and internal–external (IE) rotation knee motions during a complete cycle of level walking. Relative ranges of motion and timing of key points within the in vivo motion data were compared against the same ranges and same key points from the input profiles of the displacement-controlled wear testing standard ISO14243-3. The subjects exhibited a FE pattern similar to ISO, with an insignificant difference in range of FE rotation from midstance to terminal stance. However, the subjects had a significantly higher range of knee flexion from terminal stance into swing. The subjects also exhibited a phase delay for the entire gait cycle. For AP translation, the standard profile had statistically significant lower magnitudes than seen in vivo. Opposite pattern of AP motion was also apparent from midstance and swing. Similarly, ISO specified a smaller IE total range of rotation with a motion pattern in complete opposition to that seen in vivo. In conclusion, significant differences were found in both the magnitudes and pattern of in vivo motion compared with ISO.     

MR水激励序列显示膝关节软骨的临床应用研究

目的：探讨三维快速梯度回波水激励膝关节软骨成像序列（3D-FFE-WATS）相对于三维快速梯度回波预饱和反转恢复法脂肪抑制序列（3D-FFE-SPIR）在显示膝关节软骨方面的优势,选择显示膝关节软骨的最佳序列。方法：应用3D-FFE-WATS及3D-FFE-SPIR序列组合对20名志愿者及30例疑诊关节软骨损伤的单膝关节进行检查,获得膝关节各软骨的3D图像,并利用3D最大密度投影法（MIP）进行横断面和冠状面3D重建。分析上述2种序列对软骨病变的显示及检出能力,计算其对关节软骨的信噪比（SNR）和对比噪声比（CNR）,并进行统计学分析。结果：两序列在显示膝关节软骨SNR方面,无统计学意义（P〉0.05）;两种序列在显示软骨与关节液的CNR、软骨与骨皮质的CNR、软骨与骨髓的CNR、软骨与肌肉的CNR差异方面t值分别为（-30.619;2.348;-2.408;2.216）,有统计学意义（P〈0.05）。结论：3D-FFE-WATS序列可作为膝关节软骨成像的首选序列。     

Can generic knee joint models improve the measurement of osteoarthritic knee kinematics during squatting activity?

Knee joint kinematics derived from multi-body optimisation (MBO) still requires evaluation. The objective of this study was to corroborate model-derived kinematics of osteoarthritic knees obtained using four generic knee joint models used in musculoskeletal modelling – spherical, hinge, degree-of-freedom coupling curves and parallel mechanism – against reference knee kinematics measured by stereo-radiography. Root mean square errors ranged from 0.7° to 23.4° for knee rotations and from 0.6 to 9.0 mm for knee displacements. Model-derived knee kinematics computed from generic knee joint models was inaccurate. Future developments and experiments should improve the reliability of osteoarthritic knee models in MBO and musculoskeletal modelling.     

重组人中期因子midkine对大鼠膝关节软骨部分损伤的修复作用

目的:通过外源注射不同剂量的重组人中期因子midkine(rhMK),研究其对大鼠膝关节软骨部分损伤的修复作用。方法:雄性SD大鼠双侧膝关节建立软骨部分损伤的动物模型,术后24小时分别向关节腔内注射生理盐水或rhMK (20μg/kg、60μg/kg、180μg/kg)。于术后8周将大鼠全部处死,取材进行组织学观察,从而确定最佳注射剂量;在药代动力学研究中,按最佳注射剂量向正常大鼠膝关节腔内注射rhMK,分别于注射后1小时、1天、3天、6天、9天、12天和15天处死大鼠,检测膝关节软骨组织中rhMK的含量。结果:不同剂量的重组蛋白对膝关节软骨部分损伤均有不同程度的修复作用,其中180μg/kg的剂量效果最佳;以180μg/kg的剂量向正常大鼠膝关节腔内注射rhMK后,经过Kinetica5.0药代动力学软件拟合后,计算得rhMK在软骨组织中的消除相半衰期为8.69天。结论:rhMK对大鼠膝关节软骨部分损伤有明显的修复作用,最佳注射剂量为180μg/kg,最佳注射时间间隔为8天。     

The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis

Objective: Idiopathic osteoarthritis is the most common form of osteoarthritis (OA) world-wide and remains the leading cause of disability and the associated socio-economic burden in an increasing aging population. Traditionally, OA has been viewed as a degenerative joint disease characterized by progressive destruction of the articular cartilage and changes in the subchondral bone culminating in joint failure. However, the etiology of OA is multifactorial involving genetic, mechanical and environmental factors. Treatment modalities include analgesia, joint injection with steroids or hyaluronic acid, oral supplements including glucosamine and chondroitin sulfate, as well as physiotherapy. Thus, there is significant interest in the discovery of disease modifying agents. One such agent, glucosamine (GlcN) is commonly prescribed even though the therapeutic efficacy and mechanism of action remain controversial. Inflammatory cytokines, including IL-1β, and proteinases such as MMP-13 have been implicated in the pathogenesis and progression of OA together with an associated CpG demethylation in their promoters. We have investigated the potential of GlcN to modulate NF-kB activity and cytokine-induced abnormal gene expression in articular chondrocytes and, critically, whether this is associated with an epigenetic process. Method: Human chondrocytes were isolated from the articular cartilage of femoral heads, obtained with ethical permission, following fractured neck of femur surgery. Chondrocytes were cultured for 5 weeks in six separate groups; (i) control culture, (ii) cultured with a mixture of 2.5 ng/ml IL-1β and 2.5 ng/ml oncostatin M (OSM), (iii) cultured with 2 mM N-acetyl GlcN (Sigma–Aldrich), (iv) cultured with a mixture of 2.5 ng/ml IL-1β, 2.5 ng/ml OSM and 2 mM GlcN, (v) cultured with 1.0 μM BAY 11-7082 (BAY; NF-kB inhibitor: Calbiochem, Darmstadt, Germany) and, (vi) cultured with a mixture of 2.5 ng/ml IL-1β, 2.5 ng/ml OSM and 1.0 μM BAY. The levels of IL1B and MMP13 mRNA were examined using qRT-PCR. The percentage DNA methylation in the CpG sites of the IL1β and MMP13 proximal promoter were quantified by pyrosequencing. Result:IL1β expression was enhanced over 580-fold in articular chondrocytes treated with IL-1β and OSM. GlcN dramatically ameliorated the cytokine-induced expression by 4-fold. BAY alone increased IL1β expression by 3-fold. In the presence of BAY, IL-1β induced IL1B mRNA levels were decreased by 6-fold. The observed average percentage methylation of the -256 CpG site in the IL1β promoter was 65% in control cultures and decreased to 36% in the presence of IL-1β/OSM. GlcN and BAY alone had a negligible effect on the methylation status of the IL1B promoter. The cytokine-induced loss of methylation status in the IL1B promoter was ameliorated by both GlcN and BAY to 44% and 53%, respectively. IL-1β/OSM treatment increased MMP13 mRNA levels independently of either GlcN or BAY and no change in the methylation status of the MMP13 promoter was observed. Conclusion: We demonstrate for the first time that GlcN and BAY can prevent cytokine-induced demethylation of a specific CpG site in the IL1β promoter and this was associated with decreased expression of IL1β. These studies provide a potential mechanism of action for OA disease modifying agents via NF-kB and, critically, demonstrate the need for further studies to elucidate the role that NF-kB may play in DNA demethylation in human chondrocytes.     

The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain

Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.