Modulation of receptor sensitivity: possible therapeutic target?

Ischaemic preconditioning and post-conditioning are cardioprotective interventions that salvage ischaemic myocardium and reduce infarct size. Yet this cardioprotective effect is not the sole response of the heart to ischaemic preconditioning and post-conditioning. It was known that protein kinase C activation in the signalling cascade of ischaemic preconditioning increased the affinity of the adenosine A_2b receptor so that much lower concentrations of adenosine caused A_2b receptor-dependent signalling. In this issue of the British Journal of Pharmacology, these cardioprotective interventions are shown to block desensitization of surface receptors on the sarcolemma of the cardiomyocyte and this receptor effect is divorced from any cardioprotection. Modulating receptor function through signalling pathways is a novel idea but, currently, whether these observations have any clinical relevance is not known. Additional investigations are warranted to determine whether this effect on receptors can be generalized to other surface receptors, and whether the effect can be harnessed to improve treatment of the patient with acute myocardial infarction.     

间断性PTHrP对成牙骨质细胞凋亡及矿化的影响

目的 探讨间歇性甲状旁腺激素相关蛋白(parathyroid hormone related protein, PTHrP)刺激在成牙骨质细胞中对细胞凋亡和成牙骨质矿化相关蛋白和细胞因子表达的影响。方法 应用成牙骨质细胞OCCM-30,使用PTHrP(1-36)、甲状旁腺激素I型受体(parathyroid hormone type I receptor, PTH1R)阻断剂PTHrP(7-34)对细胞进行间歇性刺激,间歇性给药模式包含3个周期,48 h/周期,分为对照组、PTHrP(1-36)组及 PTH1R阻断剂组。采用流式细胞术检测细胞凋亡;采用茜素红染色观察矿化功能;采用real-time PCR和Western blotting法检测细胞内成牙骨质矿化相关蛋白-骨桥素(osteopontin, OPN)、I型胶原蛋白(collagen-1, COL-1)及成牙骨质相关细胞因子I型胰岛素样生长因子-1(insulin like growth factor-1, IGF-1)的基因表达及蛋白质表达。结果 间断性PTHrP抑制成牙骨质细胞凋亡,PTH1R阻断剂促进成牙骨质细胞凋亡(P<0.05);PTHrP间断性刺激能够显著增加成牙骨质细胞内OPN、COL-1、IGF-1基因及蛋白表达(P<0.05);PTH1R阻断剂抑制成牙骨质细胞内OPN、COL-1、IGF-1基因及蛋白表达(P<0.05)。结论 间断性PTHrP可通过与成牙骨质细胞上PTH1R相互作用抑制细胞凋亡,促进成牙骨质细胞矿化以及相关蛋白和细胞因子的表达。     

甲状旁腺素相关蛋白对小鼠颌骨来源成骨细胞增殖分化的影响

目的观察甲状旁腺素相关蛋白(PTHrP)对体外培养小鼠颌骨来源的成骨细胞增殖和分化的影响。方法用出生1~2 d小鼠的颌骨,分离培养出成骨细胞,用PTHrP处理,分间歇或连续两种给药方法处理细胞,以四甲基偶氮唑蓝(MTT)法检测细胞增殖,以碱性磷酸酶含量测定和矿化结节计数检测细胞的分化。结果两种给药方式MTT增殖结果均高于对照组,但连续给药组碱性磷酸酶含量和钙化结节计数与对照组无明显差异,间歇给药组则均高于对照组。结论PTHrP间歇给药具有促进颌骨来源成骨细胞增殖和分化的作用,而连续给药则只能促进其增殖,对分化影响不明显。     

辛伐他汀对PTHrP诱导的破骨细胞性骨吸收及小鼠颅盖骨代谢的影响

[目的]探讨辛伐他汀对体外甲状旁腺素相关肽（PTHrP）诱导小鼠的破骨细胞骨吸收功能的作用及其小鼠骨代谢的影响。[方法]采用PTHrP诱导小鼠骨髓细胞培养破骨细胞和小鼠颅盖骨培养体系，检测辛伐他汀作用8d后破骨细胞骨吸收陷窝和培养上清钙的变化；检测小鼠颅盖骨培养上清碱性磷酸酶和钙含量，组织学观察小鼠颅盖骨形态学变化。[结果]辛伐他汀体外可明显抑制PTHrP诱导小鼠的破骨细胞骨吸收陷窝的形成及培养上清钙的释放，辛伐他汀体外可增强小鼠颅盖骨培养上清碱性磷酸酶的活性，组织学观察到辛伐他汀使小鼠颅盖骨矿化增强。[结论]辛伐他汀体外不仅可促进小鼠颅盖骨的成骨活性，并且可明显抑制PTHrP诱导小鼠的破骨细胞骨吸收功能，对骨吸收性疾病有着重要的防治作用。     

Hypercalcaemia in Systemic Lupus Erythematosus

Hypercalcaemia is a common electrolyte abnormality. The vast majority of patients will be shown to have either hyperparathyroidism or malignancy. In less than 10% of patients other, less common causes of hypercalcaemia will be present. Systemic lupus erythematosus is a very rare cause of hypercalcaemia. It may be associated with lymphadenopathy and pleuritis to constitute a distinct clinical entity described as ‘hypercalcaemia–lymphoedema syndrome’. In these cases the pathophysiology of the hypercalcaemia is not completely understood. In some cases it is associated with elevated levels of parathyroid-related peptide (PTHrP). In others the level of PTHrP is normal, and it has been suggested that autoantibodies may cause hypercalcaemia by activating the PTH receptor. We describe a case of a woman who presented with severe hypercalcaemia, developed the hypercalcaemia–lymphodema syndrome and fulfilled the diagnostic criteria of systemic lupus erythematosus. Received: 30 April 2000 / Accepted: 8 November 2000     

Alteration of secretion of parathyroid hormone-related peptide and expression of its mRNA in a human hepatoma cell line (HEP G2) treated with agents that affect cell growth

Previously, using human hepatoma cells (HepG2), we found that immunoneutralization of secreted PTHrP increased cell growth. Here we asked whether PTHrP production was affected by agents that alter growth of Hep G2 cells. Immunoreactive PTHrP in medium and PTHrP mRNA expression were examined. Treatment of cells with 10 μM hydrocortisone or 1 ng/mL TGF-β1 for 72 h inhibited cell growth by 28±6 and 36±2% and increased PTHrP in medium by 128±10 and 525 ±27%, respectively. The increase in PTHrP produced by both agents was dose-and time-dependent, and the increased PTHrP was accompanied by dose-and time-dependent enhanced expression of PTHrP mRNA. In contrast, 10% fetal bovine serum (FBS) for 72 h increased cell growth by 38±6% (vs serum-free medium) and decreased PTHrP production by 49±4% whereas culture in high glucose (3–4g/L) increased cell growth by 43±1% (vs 1 g/L glucose) and decreased PTHrP by 55±0.4%. Inhibition of PTHrP by both FBS and glucose was dose-dependent; FBS also inhibited PTHrP mRNA. The results show that increased cell growth was associated with decreased PTHrP production, while decreased growth was accompanied by increased PTHrP production. The findings imply that PTHrP may help mediate growth effects of these agents on Hep G2 cells.     

Bone metastasis: Interaction between cancer cells and bone microenvironment

BackgroundBone is one of the most common target organs for cancer metastasis, especially in patients with advanced breast and prostate cancers. Despite recent advances in therapeutic approaches, bone metastases remain incurable and produce multiple complications called skeletal-related events, including hypercalcemia, pathological fractures, spinal compression, and bone pain, which are associated with poor prognosis.HighlightAlthough the precise mechanisms are yet to be fully elucidated, accumulating evidence suggests that bone provides a favorable microenvironment that enables circulating cancer cells to home, proliferate, and colonize, resulting in the formation of metastasis. Cancer cells that metastasize to bone also possess unique features, enabling them to utilize the bone microenvironment. Thus, communication between cancer cells and bone is believed to be critical for the development and progression of bone metastases.ConclusionContinued studies are warranted to understand the molecular mechanisms underlying bone metastases and to develop mechanism-based and effective therapeutic interventions.