抗骨质疏松药双膦酸酯的作用机理

正常的骨代谢是在掌管骨形成的成骨细胞和掌管骨吸收的破骨细胞这两种细胞保持平衡下进行的。骨质疏松是由于骨吸收高于骨形成而导致骨量减少的疾病。骨质疏松可通过抑制破骨细胞的形成或抑制骨吸收功能而达到预防和治疗的效果。具有P-C-P骨架结构的双膦酸酯(BP)是焦磷酸的衍生物。BP类化合物和焦磷酸一样,与钙的亲和力较高而选择性被骨所摄入。这类化合物对水解反应较稳定,从而能长期停留在骨内。BP类化合物在骨吸收过程中蓄积在破骨细胞内而抑制骨吸收。阿来屈酯(alendronate)是BP类化合物中第一个作为骨质疏松及过多的骨吸收所引起…     

辛伐他汀对体外成骨细胞、破骨细胞的影响

目的 探讨辛伐他汀对体外培养成骨细胞、破骨细胞的影响.方法 分离SD大鼠成骨细胞、破骨细胞,体外培养时给予辛伐他汀刺激,观察药物对成骨细胞增殖率和碱性磷酸酶以及骨细胞骨吸收的影响.结果 辛伐他汀10~(-6)～10~(-9)mol/L对碱性磷酸酶的分泌有明显促进作用,10~(-6)～10~(-8)mol/L的辛伐他汀既促进成骨细胞的增殖,又抑制破骨细胞的骨吸收.结论 辛伐他汀在体外促进骨形成、抑制骨吸收,有望成为治疗骨质疏松的约物.     

染料木素抗骨质疏松研究进展

染料木素作为一种"植物雌激素",能促进成骨细胞增殖、分化和矿化骨形成功能,也能够抑制破骨细胞骨吸收过程,存在多种抗骨质疏松的分子机制。该文综述染料木素抗骨质疏松作用及其机制的研究进展,为研究与开发抗骨质疏松新药提供依据。     

抗骨质疏松症药物的临床应用进展

近年来,随着社会老龄化的发展,骨质疏松症患者愈来愈多,作为一个社会问题已引起越来越多的关注.骨质疏松主要是由于骨吸收与骨形成之间的平衡被打破,骨吸收量大于骨形成量,从而引起骨量减少的一种疾病.一般认为,破骨细胞活性增强,导致骨吸收增加,是形成骨质疏松的重要原因.破骨细胞活性受多种激素和细胞因子影响,如降钙素、甲状旁腺激素、炎症因子、雌激素等.因此,目前普遍认为,治疗骨质疏松的药物应具有增强钙吸收、调节内分泌平衡及抑制骨吸收、增强骨形成的作用.本文通过对近年来有代表性的相关文献进行分析归纳,为临床合理选用提供参考.     

淫羊藿苷对破骨细胞的分化及骨吸收功能的影响

目的研究淫羊藿苷对破骨细胞的分化及骨吸收功能的影响,评价淫羊藿苷对骨质疏松的预防及治疗作用。方法采用1,25-(OH)2D3诱导兔骨髓单核细胞形成破骨细胞样细胞以及原代分离的乳兔成熟破骨细胞与骨片共培养的方法,考察淫羊藿苷对破骨细胞的分化及骨吸收功能的影响。结果浓度为100、50μmol.L-1的淫羊藿苷明显抑制1,25-(OH)2D3诱导兔骨髓单核细胞形成破骨细胞样细胞的数目,当其浓度为100、50、10μmol.L-1时,明显抑制破骨细胞的骨吸收功能,具体表现在吸收陷窝数目及表面积均明显减少。结论淫羊藿苷不仅可以明显抑制破骨细胞的分化,同时具有抑制破骨细胞的骨吸收功能的作用,提示淫羊藿苷具有改善骨吸收功能亢进的潜力。     

抗骨质疏松治疗药物研究的新进展

骨质疏松是一种常见的全身性骨代谢疾病,主要表现为骨密度与骨量的下降,从而导致继发性骨折。目前,随着其发病率不断增高,骨质疏松已经成为一个世界范围的健康问题和当前医学的研究热点。骨吸收抑制剂主要作用于破骨细胞,通过抑制破骨细胞分化成熟,减少骨吸收;骨形成促进剂主要作用于成骨细胞,激活其骨形成功能,并且有重建骨组织的效应;骨矿化物是防治骨质疏松的基础药物,包括钙剂和维生素D;解偶联剂种类较为单一,代表药物为雷尼酸锶。主要对以上四大类抗骨质疏松药物的研究进展进行介绍。     

骨新康对大鼠成骨细胞及破骨细胞活性的研究

目的:观察骨新康对新生大鼠成骨细胞及破骨细胞活性影响。方法:SD大鼠灌胃给药3 d取得含药血清。分离成骨细胞及破骨细胞体外培养,MTT法检细胞活性,AKP检测成骨细胞分化程度,用骨吸收陷窝数量评价破骨细胞活性。结果:与对照组相比,含骨新康血清剂量依赖性地促进成骨细胞增殖;与生理盐水组相比,10%,20%骨新康组含药血清显著促进成骨细胞分泌碱性磷酸酶(P<0.01),抑制骨陷窝的生成。结论:骨新康通过促进成骨细胞的增殖和分化,抑制破骨细胞的活性,对临床骨质疏松的防治具有积极意义。     

作用于成骨细胞的生物活性物质及化合物

成骨细胞和破骨细胞是骨形成和骨吸收率的决定因素。在研究甲亢与骨质疏松的关系中发现，甲状腺激素能直接刺激成骨细胞的兴奋性。体外实验发现，糖皮质激素能抑制成骨细胞的增殖与分化。雌激素可间接通过一些钙调节激素抑制骨吸收，部分研究证实雌激素能抑制成骨细胞的凋亡，一般认为雌激素的主要功能是通过雌激素受体直接诱导骨细胞的凋亡。RT－PCR和免疫组化法发现瘦素可以明显增加进入矿化状态的成骨细胞的矿化结节的数量。Na^ /Ca^2 交换抑制剂是骨基质内部小环境的调节剂，并在骨矿化过程中起关键作用。     

骨质疏松治疗的研究进展

本文为骨质疏松治疗相关研究的综述。骨质疏松症是以骨量减少和骨微结构破坏为特征,骨量减少,脆性增加和易于骨折的代谢性骨病。随着对成骨细胞和破骨细胞生理学和相关分子机制研究的不断深入,针对抑制过度的骨吸收和促进骨形成研发了新的治疗方法。其中最有应用前景的药物包括:Denosumab类药物,NF-kB配体的受体激活剂的单克隆抗体,组织蛋白酶K抑制剂,Sclerostin抗体,DKK-1抗体等。本综述将以骨生理学特点为基础,讨论骨质疏松新的治疗方法以及其潜在的生理机制。     

基于斑马鱼模型的枸杞子改善骨质疏松活性部位筛选及其机制初探

利用斑马鱼幼鱼筛选枸杞子改善骨质疏松的活性部位,并通过斑马鱼成鱼骨质疏松模型验证筛选结果。以泼尼松龙为诱导剂构建斑马鱼幼鱼及成鱼骨质疏松模型,给予枸杞子不同提取物及化学部位共9组样品,通过茜素红染色后统计第一椎骨面积及光密度值,椎骨骨节数量以筛选枸杞子抗骨质疏松的活性部位。采用茜素红染色观察斑马鱼成鱼鳞片基质矿化及骨吸收情况;采用碱性磷酸酶(ALP)和抗酒石酸酸性磷酸酶(TRAP/TRACP)染色检测鳞片中成骨细胞和破骨细胞活性;采用qRT-PCR法测定鳞片中骨代谢相关基因alp、骨桥蛋白(opn)、成骨细胞特异性转录因子(sp7)、组织蛋白酶K (ctsk)、tracp、Runx家族转录因子2b (runx2b)的表达情况。结果显示,枸杞子各样品组均能够不同程度地改善斑马鱼幼鱼第一椎骨形成面积、染色光密度值和椎骨骨节数量,其中以枸杞子多糖部位效果最优。枸杞多糖能够显著抑制斑马鱼鳞片中骨吸收陷窝的形成,增强鳞片中ALP活性,降低TRAP活性,上调alp、sp7、opn基因,下调ctsk、tracp基因的表达。研究结果表明,枸杞多糖能够调节成骨细胞与破骨细胞活性,减少骨吸收,促进骨形成,...     

Osteoblasts and osteoclasts in bone remodeling and inflammation

Bone homeostasis is maintained by a balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteoblasts not only play a central role in bone formation by synthesizing multiple bone matrix proteins, but regulate osteoclast maturation by soluble factors and cognate interaction, resulting in bone resorption. Osteoclast maturation requires stimulation by RANKL expressed on osteoblasts, and the cognate interaction is mediated by firm adhesion via ICAM-1. During the processes, pro-inflammatory cytokines such as IL-1 and TNF-alpha, cause an imbalance in bone metabolism, by favoring bone resorption via the induction of RANKL and ICAM-1 on osteoblasts. These inflammatory signals originate from the immune system, the largest source of cell-derived regulatory signals, and such immunological signals to the bone are transmitted primarily via osteoblasts to induce osteoclast maturation, resulting in secondary osteoporosis. Actually, such phenomena mainly occur at the interface between proliferating synovium and bone tissue in rheumatoid arthritis (RA). Thus, therapeutic strategies for these conditions, an anti-TNF-alpha antibody and an IL-1 receptor antagonist, effective for treating RA disease activity, also reduce secondary osteoporosis and joint destruction. Based on an improved understanding of immune signals, investigation of the suppression of cell functions may lead to improved understanding and better treatment of diseases of bone metabolism and osteoporosis.     

Advances in the treatment of osteoporosis

Drugs used to treat osteoporosis act either by inhibiting bone resorption or stimulating bone formation. Osteoclast formation and bone resorption require cell-to-cell contact between osteoblasts and osteoclast precursors and osteoclasts in the marrow. Interaction between the receptor for activation of nuclear factor kappa B (RANK) on the surface of preosteoclasts and osteoclasts and RANK ligand on the surface of osteoblasts is required to stimulate osteoclast formation and activation. Binding of the RANK ligand to its receptor and osteoclastogenesis are prevented by osteoprotegerin (OPG), a decoy receptor produced by osteoblasts and marrow stromal cells. Thus, interference in binding of the RANK ligand to RANK by OPG determines the rate of bone resorption. Antiresorptive drugs such as estrogen, raloxifene, bisphosphonates, salmon calcitonin, and osteoprotegerin increase bone mass by inhibiting osteoclast function and bone resorption. Osteoprotegerin is more potent since it also inhibits osteoclast formation. Raloxifene, a selective estrogen receptor modulator (SERM), is a member of a class of compounds that act through estrogen receptors and are agonists for bone, antagonists for breast and uterine tissue and may be cardioprotective. The drug was shown to prevent vertebral fractures. Alendronate and bisphosphonates are the only antiresorptive drugs that have been shown to decrease fracture rates for the hip in addition to spine and other sites. Bone morphogenetic proteins stimulate bone formation at local sites and are being developed to stimulate fracture healing. Parathyroid hormone (1-34) stimulates osteoblastic bone formation, markedly increases bone mass, prevents vertebral fractures and is under development to treat osteoporosis.     

葛根素防治骨质疏松症的作用机制研究进展

我国骨质疏松症的患病率高,是老年患者致残和致死的主要原因之一。葛根素是葛根中主要活性成分,可促进成骨细胞的增殖分化、抑制骨吸收和破骨细胞的分化形成、促进骨髓间充质干细胞向成骨分化、发挥雌激素样作用。综述了葛根素防治骨质疏松症的作用机制研究进展,为深入开展葛根素治疗骨质疏松症的基础研究和新药开发提供参考。     

胰高血糖素样肽-1对骨质疏松症骨代谢影响的研究进展

目的:综述胰高血糖素样肽-1(GLP-1)对骨质疏松症骨代谢影响研究进展。方法:通过查阅相关文献及临床实践经验进行总结。结果:骨质疏松症与骨代谢密切相关,GLP-1能通过多种途径降低血糖,促进骨形成和抑制骨吸收,但它对成骨细胞及破骨细胞的具体作用仍不明确。结论:GLP-1受体已被用于治疗糖尿病,GLP-1通过调节体内血糖来间接影响骨代谢,从而为治疗骨质疏松症带来了新的希望。     

Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption

OPG is a new member of the tumor necrosis factor (TNF) receptor family which plays a key role in the physiological regulation of osteoclastic bone resorption. The protein, which is produced by osteoblasts and marrow stromal cells, lacks a transmembrane domain and acts as a secreted decoy receptor which has no direct signaling capacity. OPG acts by binding to its natural ligand OPGL, which is also known as RANKL (receptor activator of NF-kappaB ligand). This binding prevents OPGL from activating its cognate receptor RANK, which is the osteoclast receptor vital for osteoclast differentiation, activation and survival. Overexpression of OPG in transgenic mice leads to profound osteopetrosis secondary to a near total lack of osteoclasts. Conversely, ablation of the OPG gene causes severe osteoporosis in mice. Ablation of OPGL or RANK also produces profound osteopetrosis, indicating the important physiological role of these proteins in regulating bone resorption. The secretion of OPG and OPGL from osteoblasts and stromal cells is regulated by numerous hormones and cytokines, often in a reciprocal manner. The relative levels of OPG and OPGL production are thought to ultimately dictate the extent of bone resorption. Excess OPGL increases bone resorption, whereas excess OPG inhibits resorption. Recombinant OPG blocks the effects of virtually all factors which stimulate osteoclasts, in vitro and in vivo. OPG also inhibits bone resorption in a variety of animal disease models, including ovariectomy-induced osteoporosis, humoral hypercalcemia of malignancy, and experimental bone metastasis. OPG might represent an effective therapeutic option for diseases associated with excessive osteoclast activity.     

The Pharmacology and Therapeutic Utility of Bisphosphonates

Bisphosphonates have clinical application in diseases associated with increased bone turnover that inhibit osteoclast-mediated bone resorption by direct and indirect actions on osteoblasts and macrophages. Bisphosphonates are the treatment of choice for Paget's disease of bone, in which they return to normal the increased rate of bone turnover and slow radiographic disease progression. The agents reduce hypercalcemia associated with malignancy, and may reduce bone pain and prevent radiographic progression of metastatic bone disease. In patients with postmenopausal osteoporosis, they prevent further bone loss and reduce fracture rates. The drugs also ameliorate osteoporosis associated with long-term corticosteroid treatment. Bisphosphonates are well tolerated; gastrointestinal disturbances are the most common adverse events. Potential bone mineralization defects that occur with first-generation bisphosphonates are not of concern with therapeutic doses of newer ones.     

Effects of methylprednisolone on bone formation and resorption in rats

Excessive glucocorticoids induce osteoporosis. However, there is some controversy regarding the mechanism of action, and even the endpoint result. The present study was carried out to obtain further insight into the action of glucocorticoids on bone formation and resorption in rats. Growing rats were injected subcutaneously with methylprednisolone (mPSL) at doses of 0, 2.5, 5, 10 or 20 mg/kg per day for 4 weeks. Bone mineral density (BMD), enchondral and periosteal bone formation, collagen synthetic activities of osteoblasts, numbers of osteoblasts and osteoclasts, and serum markers to assess bone turnover were determined. Administration of mPSL dose-dependently increased the BMD in the tibial metaphysis, while it dose-dependently decreased the BMD in the diaphysis. Both enchondral and periosteal bone formation were decreased in a dose-dependent fashion. The incorporation and secretion of (3)H-proline by osteoblasts were both decreased in trabecular and cortical bones. The number of osteoclasts, together with the number of osteoblasts, in the tibial metaphysis was drastically decreased. Serum alkaline phosphatase and osteocalcin were decreased at higher doses. These results support the recent notion that glucocorticoids inhibit both bone formation and resorption. In addition, BMD as an endpoint result might differ from site to site in bone due to a different balance between bone formation and resorption.     

骨元肽结肠溶胶囊对去卵巢大鼠骨质疏松症的防治作用

目的探讨骨元肽结肠溶胶囊对去卵巢大鼠引起骨质疏松症的防治作用。方法采用切除大鼠双侧卵巢的方法建立大鼠骨质疏松症模型,以雌二醇(E2)作阳性对照,用放射免疫法检测大鼠血清中E2、骨钙素(BGP)、转化生长因子(TGF-β1);用生物化学的方法检测大鼠血清中碱性磷酸酶(ALK)、钙(Ca)、磷(P)和24h尿Ca、P,同时采用骨矿密度检测仪测定骨密度(BMD)。结果骨元肽结肠溶胶囊组可明显提高血清中E2、TGF-β,增加BMD,降低血清中ALK、BGP和24h尿Ca、P含量。结论骨元肽结肠溶胶囊具有提高雌激素作用,可有效抑制骨吸收,降低骨转化率,加强成骨细胞活性,增加骨密度。对去卵巢引起的大鼠骨质疏松症具有明显的防治作用。     

Myricetin Loaded Nano-micelles Delivery System Reduces Bone Loss Induced by Ovariectomy in Rats Through Inhibition of Osteoclast Formation

In recent years, much attention has been paid to the therapeutic effects of phytochemicals on osteoporosis. Other studies have shown that myricetin (MY) could promote osteogenic activity and inhibit osteoclastic effect, albeit little is known about effect of MY micellar system on osteoporosis. Therefore, we sought to discuss the therapeutic effect and mechanism of MY-loaded bone-targeting micelles on osteoporosis induced by ovariectomy (OVA) in rats. The AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles were prepared via ethanol injection method, while in vitro release study, bone targeting, pharmacokinetic studies, and the effect on proliferation of osteoblasts were investigated. Further, the therapeutic effect on osteoporosis was studied through ovariectomized rats. Compared with free MY, oral bioavailability of AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles in rats was increased by 3.54 times. The AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles exhibited bone targeting potential, and could significantly increase the activity of alkaline phosphatase and promote the proliferation of osteoblasts. Importantly, AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles mainly regulated bone metabolism by inhibiting bone resorption, thereby improving the symptoms of osteoporosis in OVA rats. The AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles substantially enhanced the oral bioavailability of MY and demonstrated good bone targeting capability, thereby suggesting its prospect as carrier for osteoporotic improvement in OVA rats.     

Arsenic induces cell apoptosis in cultured osteoblasts through endoplasmic reticulum stress

Osteoporosis is characterized by low bone mass resulting from an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, decreased bone formation by osteoblasts may lead to the development of osteoporosis, and rate of apoptosis is responsible for the regulation of bone formation. Arsenic (As) exists ubiquitously in our environment and increases the risk of neurotoxicity, liver injury, peripheral vascular disease and cancer. However, the effect of As on apoptosis of osteoblasts is mostly unknown. Here, we found that As induced cell apoptosis in osteoblastic cell lines (including hFOB, MC3T3-E1 and MG-63) and mouse bone marrow stromal cells (M2-10B4). As also induced upregulation of Bax and Bak, downregulation of Bcl-2 and dysfunction of mitochondria in osteoblasts. As also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosolic-calcium levels. We found that As increased the expression and activities of glucose-regulated protein 78 (GRP78) and calpain. Transfection of cells with GRP78 or calpain siRNA reduced As-mediated cell apoptosis in osteoblasts. Therefore, our results suggest that As increased cell apoptosis in cultured osteoblasts and increased the risk of osteoporosis.