未经证实:膝骨关节炎(KOA)是一种非常普遍的肌肉骨骼疾病,其特征是软骨退化和软骨下骨(SCB)的异常重塑。特立帕肽(PTH(1-34))是治疗骨质疏松症(OP)的有效合成代谢药物,可调节骨保护素(OPG)/核因子配体受体激活剂(RANKL)/RANK信号传导,其还通过改善软骨降解和抑制SCB的异常重塑而对KOA具有治疗作用。然而,PTH(1-34)治疗KOA的机制仍不确定,有待进一步探讨.因此,我们比较了PTH(1-34)对创伤后KOA小鼠模型的影响,以探讨其潜在的治疗作用和机制.
未经证实:体内研究,研究并比较了八周大的雄性小鼠,包括野生型(WT)(n=54)和OPG-/-(n=54)。创伤后KOA模型是通过内侧半月板(DMM)的失稳建立的。WT小鼠被随机分为三组:假手术组(WT-sham;n=18),DMM组(WT-DMM;n=18),和PTH(1-34)治疗组(WT-DMM+PTH(1-34);n=18)。同样,OPG-/-小鼠也被随机分为三组。设计的老鼠在4号被处死,8th,和第12周评估KOA进展。为了进一步探讨PTH(1-34)的软骨保护作用,用不同浓度的PTH(1-34)体外刺激ATDC5软骨细胞。
UNASSIGNED:与WT-sham小鼠相比,在WT-DMM小鼠中检测到软骨厚度降低和糖胺聚糖(GAG)损失方面的显著的软骨磨损。PTH(1-34)通过减轻磨损表现出软骨保护作用,保留厚度和GAG含量。此外,PTH(1-34)治疗后,SCB的恶化得到缓解,PTH1R/OPG/RANKL/RANK的表达增加。在OPG-/-小鼠中,DMM小鼠的软骨表现出典型的KOA改变,具有较高的OARSI评分和较薄的软骨。软骨损伤减轻,但SCB的异常重塑对PTH(1-34)治疗没有任何反应。与WT-DMM小鼠相比,OPG-/-DMM小鼠用较薄的软骨捕获了更具侵略性的KOA,严重的软骨损伤,SCB的异常重塑较多。此外,WT-DMM小鼠和OPG-/-DMM小鼠的受损软骨均得到缓解,但在给予PTH后,WT-DMM小鼠中只有SCB的恶化得到缓解(1-34)。体外研究,PTH(1-34)可以促进软骨细胞的活力,增强细胞外基质(ECM)的合成(AGC,COLII,和SOX9)在mRNA和蛋白质水平,但抑制炎性细胞因子(TNF-α和IL-6)的分泌。
UNASSIGNED:在WT小鼠中,软骨的磨损均减轻,SCB的异常重塑受到抑制,但在OPG-/-小鼠中仅观察到软骨保护作用。PTH(1-34)通过在体内减缓软骨退变以及通过在体外促进软骨细胞的增殖和增强ECM合成而表现出软骨保护作用。当前的研究表明,受干扰的SCB的抢救取决于OPG的调节,而软骨保护作用与OPG的调节无关。这为KOA的治疗提供了证据。
UNASSIGNED:全身给药PTH(1-34)可以不同的机制对软骨和SCB产生治疗作用,以缓解KOA进展,这可能是KOA的一种新疗法。
UNASSIGNED: Knee osteoarthritis (KOA) is a highly prevalent musculoskeletal disorder characterized by degeneration of cartilage and abnormal remodeling of subchondral bone (SCB). Teriparatide (PTH (1-34)) is an effective anabolic drug for osteoporosis (OP) and regulates osteoprotegerin (OPG)/receptor activator of nuclear factor ligand (RANKL)/RANK signaling, which also has a therapeutic effect on KOA by ameliorating cartilage degradation and inhibiting aberrant remodeling of SCB. However, the mechanisms of PTH (1-34) in treating KOA are still uncertain and remain to be explored. Therefore, we compared the effect of PTH (1-34) on the post-traumatic KOA mouse model to explore the potential therapeutic effect and mechanisms.
UNASSIGNED: In vivo study, eight-week-old male mice including wild-type (WT) (n = 54) and OPG-/- (n = 54) were investigated and compared. Post-traumatic KOA model was created by destabilization of medial meniscus (DMM). WT mice were randomly assigned into three groups: the sham group (WT-sham; n = 18), the DMM group (WT-DMM; n = 18), and the PTH (1-34)-treated group (WT-DMM + PTH (1-34); n = 18). Similarly, the OPG-/- mice were randomly allocated into three groups as well. The designed mice were executed at the 4th, 8th, and 12th weeks to evaluate KOA progression. To further explore the chondro-protective of PTH (1-34), the ATDC5 chondrocytes were stimulated with different concentrations of PTH (1-34) in vitro.
UNASSIGNED: Compared with the WT-sham mice, significant wear of cartilage in terms of reduced cartilage thickness and glycosaminoglycan (GAG) loss was detected in the WT-DMM mice. PTH (1-34) exhibited cartilage-protective by alleviating wear, retaining the thickness and GAG contents. Moreover, the deterioration of the SCB was alleviated and the expression of PTH1R/OPG/RANKL/RANK were found to increase after PTH (1-34) treatment. Among the OPG-/- mice, the cartilage of the DMM mice displayed typical KOA change with higher OARSI score and thinner cartilage. The damage of the cartilage was alleviated but the abnormal remodeling of SCB didn\'t show any response to the PTH (1-34) treatment. Compared with the WT-DMM mice, the OPG-/--DMM mice caught more aggressive KOA with thinner cartilage, sever cartilage damage, and more abnormal remodeling of SCB. Moreover, both the damaged cartilage from the WT-DMM mice and the OPG-/--DMM mice were alleviated but only the deterioration of SCB in WT-DMM mice was alleviated after the administration of PTH (1-34). In vitro study, PTH (1-34) could promote the viability of chondrocytes, enhance the synthesis of extracellular matrix (ECM) (AGC, COLII, and SOX9) at the mRNA and protein level, but inhibit the secretion of inflammatory cytokines (TNF-α and IL-6).
UNASSIGNED: Both wear of the cartilage was alleviated and aberrant remodeling of the SCB was inhibited in the WT mice, but only the cartilage-protective effect was observed in the OPG-/- mice. PTH (1-34) exhibited chondro-protective effect by decelerating cartilage degeneration in vivo as well as by promoting the proliferation and enhancing ECM synthesis of chondrocytes in vitro. The current investigation implied that the rescue of the disturbed SCB is dependent on the regulation of OPG while the chondro-protective effect is independent of modulation of OPG, which provides proof for the treatment of KOA.
UNASSIGNED: Systemic administration of PTH (1-34) could exert a therapeutic effect on both cartilage and SCB in different mechanisms to alleviate KOA progression, which might be a novel therapy for KOA.