Objectives Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.
Dietary fatty acid (FA) content and type have different effects on obesity-associated osteoarthritis (OA), but the mechanisms underlying these differences are not fully understood. Inflammation activated by toll-like receptor 4 (TLR4)/nuclear factor- (NF-) κB signaling and pyroptosis induced by the NLRP3/caspase-1/gasdermin D (GSDMD) signaling pathway play important roles in OA development. Our aim in this study was to observe the effects of dietary FAs on the articular cartilage of obese post-traumatic OA model mice and on chondrocytes stimulated by lipopolysaccharide (LPS) and to determine whether the underlying mechanisms involve TLR4/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways. Mice were fed high-fat diets rich in various FAs and underwent surgical destabilization of the medial meniscus to establish the obesity-related post-traumatic OA model. LPS-induced SW1353 chondrosarcoma cells were used to mimic OA status in vitro, and TLR4 inhibitors or TLR4 overexpressing lentivirus was administered. Analysis using weight-matched mice and multiple regression models revealed that OA was associated with dietary FA content and serum inflammatory factor levels, but not body weight. Diets rich in n-3 polyunsaturated fatty acids (PUFAs) attenuated OA and inhibited the TLR4/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways, whereas diets rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), or n-6 PUFAs increased OA severity and activated these pathways. In vitro results for SFAs, n-6 PUFAs, and n-3 PUFAs were consistent with the animal experiments. However, those for MUFAs were not. FA effects on the NLRP3/caspase-1/GSDMD pathway were associated with the inhibition or activation of the TLR4 signaling pathway. In conclusion, diets rich in SFAs or n-6 PUFAs can exacerbate obesity-associated OA, whereas those rich in n-3 PUFAs have protective effects against this disease, due to their respective pro-/anti-inflammatory and pyroptotic effects. Further research on dietary FA supplements as a potential therapeutic approach for OA is needed.
Objective To explore the effect of age on the osteoporosis induced by ovariectomy in rats.Methods Each sixteen Wistar female rats about three or six months old,were divided into sham operation group and ovariectomized group respectively.The ovariectomized groups underwent bilateral ovariectomy by dorsal approach.Six months after surgery,the rats bone mass density,bone mineral content,biomechanics proporties of femurs and morphosis of distal femurs were measured to assess osteoporosis.Results Compared to corresponding sham operation group,the ovariectomized rats had a significantly decreases in body and spine BMD,BMC,maximum compress load,maximum compress stress and elastic modulus of femurs(P0.01),the morphosis of trabecula under epiphyseal plate in distal femur was raritas;the conjunction of trabecular was worsen,and the volume of trabecular decreased significantly.The six months old rats lost more bone than that in three months old rats.Conclusion Six months after surgery,both three months and six months old rats developed osteoporosis.The six months old rats had lost more bone.
Background: Er-Xian Decoction (EXD) is one of the traditional Chinese medicine (TCM) with unique effect on osteoporosis, menopausal syndrome and delayed puberty in China for many years. Objective: We aim to evaluate the potential activity of starting hypothalamic-pituitary-testicular (HPT) axis of male rats with delayed puberty. Materials and Methods : Delayed puberty model of male Sprague-Dawley (SD) rats were established with soy isoflavones (90 mg·kg -1 ) and were treated by EXD extract at doses of 5, 10 g·kg -1 or Testosterone undecanoate (TU) for 8 weeks. Body weight, body length, testis weight, T, E 2 and luteinizing hormone (LH) in serum, gonadotropin releasing hormone (GnRH) in hypothalamus, follicle stimulating hormone (FSH) and LH in pituitary gland were determined by ELISA. Immunohistochemistry was used to detect LH in pituitary gland . Results: Soy isoflavones could significantly decrease body weight, body length, testicular organ coefficient T in serum, GnRH in hypothalamus, FSH and LH in pituitary gland. Both of EXD and TU could improve the condition. E 2 and LH in serum of all groups were non-significance of difference (P > 0.05). The immunohistochemical results were well consistent with LH in pituitary gland. Conclusion: The results of the present research indicate that EXD extract is effective to start the HPT axis in puberty and can significantly improve sexual developmental inhibition caused by soy isoflavones.
Objective To observe the protective effect of rhein-estrone,a novel hybrid compound of estrone and rhein,on the bone quality of ovariectomized(OVX) rats and its estrogen-like effect on the uterine,for evaluating its anti-osteoporosis activity.Methods Forty-eight 6-month-old wistar unpregnant female rats were divided into sham operating group,OVX model group,estrone group,rhein-estrone groups with high-,moderate-,or low-dose of rhein-estrone.Rats were ovariectomized in all groups except in sham operating group.After a 24-week drug administration,rat bone mineral density of the whole body and the spine,bone mineral content(BMC),biomechanic proporties of the femur,contents of hydroxyproline and calcium,morphology of the distal femur and the uterus were examined.Results Compared to ovariectomized model rats,a significant increase in BMD of total body and the spine,BMC,maximum compress load,maximum compress stress,contents of hydroxyproline,and bone volume of the trabecular bone were observed in rats treated with three dosages of rhein-estrone(P0.05 or P0.01).Except for low bone volume compared to that in estrone group,other parameters were not defferent.The weight,diameter and endometrium thickness of the uterus in rats treated with three dosages of rhein-estrone were significantly less than those in estrone and sham groups,but were no difference compared to those in OVX model group.Conclusion Rhein-estrone significantly improved bone quality of OVX rats in the range of experimental dosages,as did by estrone.But its stimulating effect on the uterus was far less than estrone's.
Objective To investigate the kinetic changes and effect of blood brain barrier function during experimental autoimmune encephalomyelitis (EAE) in rats. Methods Albumin in serum and CSF samples of EAE rats were examined on the days of 4, 6, 8, 10, 12, 14, 16, 18 and 20 p.i.. The integrity of blood brain barrier was assessed by calculating CSF to serum albumin quotient (QA). Results The increase of QA on day 8 p.i. was prior to development of clinical symptoms. QA of EAE rats showed dynamic changes with days p.i. and there was a markedly positive correlation between clinical scores and QA (r=0 81,P=0 001). Conclusions Blood brain barrier damage during the earlier period of EAE might play an important role in the pathogenesis of EAE.
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