骨代谢调控的垂体-骨轴机制

近年来,垂体激素包括促甲状腺激素、FSH、促肾上腺皮质激素以及催产素等,相继被发现对骨代谢具有直接的调控作用.这一发现打破了垂体激素是通过作用于靶内分泌腺间接对骨代谢进行调节的传统观念,从而提出了骨代谢调控的垂体-骨轴(pituitary-bone axis)新概念.这些突破性研究进展使人们对垂体激素的功能有了全新的了解,并且对甲亢、绝经、妊娠等引起的骨质疏松症以及糖皮质激素引起的骨坏死的发病机制有了更深的认识,为相关骨代谢疾病的防治以及新药研发提供了新的科学思路和理论基础.

Abstract：

Recent studies have shown that pituitary hormones, including thyroid stimulating hormone (TSH), follicle stimulating hormone(FSH), adrenocorticotropic hormone(ACTH), and oxytocin(OT)may actually bypass their target endocrine organs and affect the skeleton directly. Therefore, a new conception, pituitary-bone axis is proposed. This breakthrough sheds a new light on the function of pituitary hormones and the pathogenesis of osteoporosis associated with hyperthyroidism, menopause or pregnancy, and even osteonecrosis after using glucocorticoids. In addition, it is conducive to give the reference guidance for clinical treatment of metabolic bone diseases and new drug development.     

Mechanisms of myocardial regeneration

Traditionally, the adult heart has been viewed as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at birth and these cells persist throughout the life span of the organ and organism. However, the discovery that cardiac stem cells live in the heart and differentiate into the various cardiac cell lineages has dramatically changed our understanding of myocardial biology. Deciphering the biological processes that lead to myocyte renewal is a challenging task. Cardiac regeneration may be accomplished by (1) commitment of multipotent stem cells that generate all specialized lineages within the parenchyma, (2) activation of unipotent progenitors with restricted differentiation potential, (3) replication of pre-existing differentiated cells, (4) transdifferentiation of exogenous progenitors that undergo plastic conversion into cells different from the organ of origin, and (5) dedifferentiation of cardiomyocytes that re-enter the cell cycle and divide. These multiple mechanisms of cell growth may act in concert to regenerate complex structures and restore the function of the target organ.     

The future of cell therapy for myocardial regeneration

There are a number of promising cell therapy products under development for the treatment of heart failure, whether due to myocardial infarction or cardiomyopathy. Looking forward beyond current products in development, there are a multitude of possibilities that hold significant promise; however, cell-based therapies present challenges that are unique to this platform. Results from transplant studies can often be misleading and need to be interpreted in the context of fundamental biologic properties of cells and development. Provided here is a summary of the current and future developments in the field of cell therapy for cardiac regeneration along with some critical insights to interpret the multitude of studies recently undertaken. Summarized are both clinical and preclinical studies that should serve as a useful entrée into this exciting new field of therapeutic development.     

Cellular cardiomyoplasty for myocardial regeneration

The evolving challenge of managing patients with congestive heart failure is the need to develop new therapeutic strategies. The cellular, molecular, and genetic approaches investigated aim to reinforce the weak, failing heart muscle while restoring its functional potential. This approach is principally cellular therapy (i.e. cellular cardiomyoplasty), the preferred therapeutic choice because of its clinical applicability and regenerative capacity. Different stem cells: bone marrow cells, skeletal and smooth muscle cells, vascular endothelial cells, mesothelial cells, adipose tissue stroma cells, dental stem cells, and embryonic and fetal cells, have been proposed for regenerative medicine and biology. Stem cell mobilization with G-CSF cytokine was also proposed as a single therapy for myocardial infarction. We investigated the association of cell therapy with electrostimulation (dynamic cellular cardiomyoplasty), the use of autologous human serum for cell cultures, and a new catheter for simultaneous infarct detection and cell delivery. Our team conducted cell-based myogenic and angiogenic clinical trials for chronic ischemic heart disease. Cellular cardiomyoplasty constitutes a new approach for myocardial regeneration; the ultimate goal is to avoid the progression of ventricular remodeling and heart failure for patients presenting with ischemic and non-ischemic cardiomyopathies.     

Stem cells for myocardial regeneration

Stem cells are being investigated for their potential use in regenerative medicine. A series of remarkable studies suggested that adult stem cells undergo novel patterns of development by a process referred to as transdifferentiation or plasticity. These observations fueled an exciting period of discovery and high expectations followed by controversy that emerged from data suggesting cell-cell fusion as an alternate interpretation for transdifferentiation. However, data supporting stem cell plasticity are extensive and cannot be easily dismissed. Myocardial regeneration is perhaps the most widely studied and debated example of stem cell plasticity. Early reports from animal and clinical investigations disagree on the extent of myocardial renewal in adults, but evidence indicates that cardiomyocytes are generated in what was previously considered a postmitotic organ. On the basis of postmortem microscopic analysis, it is proposed that renewal is achieved by stem cells that infiltrate normal and infarcted myocardium. To further understand the role of stem cells in regeneration, it is incumbent on us to develop instrumentation and technologies to monitor myocardial repair over time in large animal models. This may be achieved by tracking labeled stem cells as they migrate into myocardial infarctions. In addition, we must begin to identify the environmental cues that are needed for stem cell trafficking and we must define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will we be able to regulate this process and begin to realize the full potential of stem cells in regenerative medicine.     

The role of bone marrow stem cells in liver regeneration

Hepatic oval cells involved in some forms of liver regeneration express many markers also found on hematopoietic stem cells (HSCs). In addition, multiple independent reports have demonstrated that bone marrow cells can give rise to several hepatic epithelial cell types, including oval cells, hepatocytes, and duct epithelium. These observations have resulted in the hypothesis that bone marrow resident stem cells, specifically HSCs, are an important source for liver epithelial cell replacement, particularly during chronic injury. The function of such stem cells in hepatic injury responses is the topic of this article. Taken together, the published data on the role of bone marrow stem cells in liver damage suggest that they do not play a significant physiological role in the replacement of epithelial cells in any known form of hepatic injury. Fully functional bone marrow-derived hepatocytes exist but are extremely rare and are generated by cell fusion, not stem cell differentiation. Nonetheless, bone marrow-derived cells may play important indirect roles in liver regeneration. First, they may serve as a source for the replacement of endothelial cells. Second, hematopoietic cells, including lymphocytes, neutrophils, macrophages, and platelets, may provide crucial factors required for efficient healing of damaged liver.     

Changing axis deviation and acute myocardial infarction

Changing axis deviation has been rarely reported also during atrial fibrillation or atrial flutter. Changing axis deviation has been also rarely reported during acute myocardial infarction associated with atrial fibrillation too or at the end of atrial fibrillation during acute myocardial infarction. We present a case of changing axis deviation in a 77-year-old Italian woman admitted to the Cardiology Unit with an acute myocardial infarction. Also this case focuses attention on changing axis deviation and acute myocardial infarction.     

Stem cells and myocardial regeneration.

The belief that organs such as the heart could only undergo hypertrophy but not hyperplasia has been challenged with the discovery that differentiated cells can be constantly regenerated by stem cells (SCs). The dogma considering the heart as a post-mitotic organ has been questioned by the demonstration of continuous renewal of cardiomyocytes produced by cardiac SC differentiation and by bone marrow SCs. Several experimental models for transplantation of SCs into damaged myocardium have been developed. This new strategy is known as cellular cardiomyoplasty (CCM). CCM may be beneficial in improving cardiac function using various SC types, although many questions remain unanswered. Nonetheless, it is expected that their clinical potential will radically modify the therapeutic approach to certain cardiac diseases. In this review, we will focus on the different types of SCs tested in the heart, their advantages and limitations, and their potential therapeutic applications.     

Autologous skeletal myoblasts for myocardial regeneration

We overview the current knowledge about the use of skeletal myoblasts in regeneration of infarcted myocardium. Myoblasts are attractive candidates for cell source for cardiomyoplasty in chronic postmyocardial injury as indicated by experimental and initial clinical experience. We also review the recent developments in skeletal myoblasts transplantation techniques with special attention to percutaneous transvenous approach to deliver therapeutic agents into myocardium from the lumen of coronary veins under intravascular guidance.     

促进心肌梗死区心肌再生的组织工程研究

近年来,我国冠心病的发病率不断上升,冠状动脉旁路移植术（CABG）的病例数逐年增加,随着手术技术逐渐完善,辅助装置在部分重症病例的成功应用,冠心病的外科治疗效果不断提高。同时,提高CABG的远期疗效和危重症冠心病的疗效越来越受到重视。人们在不断寻找新技术与传统外科手段相结合的新的治疗方法,而材料科学与基础医学的交叉产生了组织工程的概念。     

Human embryonic stem cells for myocardial regeneration

Terminally differentiated adult cardiomyocytes have limited regenerative capacity and therefore any significant cell loss may result in the development of progressive heart failure. Cell replacement therapy is a promising new approach for myocardial repair but has been limited by the paucity of cell sources for functional human cardiomyocytes. The recent establishment of the human pluripotent embryonic stem (ES) cell lines may present a novel solution for this cell-sourcing problem. The ES lines were derived from human blastocysts and were shown to be capable of continuous undifferentiated proliferation, in vitro, while retaining the capability to form derivatives of all three germ layers. More recently, a reproducible cardiomyocyte differentiation system was established using these unique cells. The current review describes the derivation and properties of human ES cells and the characteristics of the cardiomyocytes derived using this unique differentiating system. The possible applications in several research and clinical areas are discussed as well as the steps required to fully harness the potential of this new technology in the fields of myocardial cell replacement and tissue engineering.     

An overview of myoblast transplantation for myocardial regeneration

Regenerative medicine represents a new frontier in treatment of disease, particularly cardiovascular disease. The contractile elements of the heart, cardiomyocytes, lack the capacity for any postnatal proliferation or regeneration. Therefore, repair of heart damage can be achieved only by manipulating cardiomyocytes to regrow or by introducing exogenous cells with the capacity to restore function to the myocardium. Many attempts have been made with various cell types to repair the damaged myocardium. We will present here a summary of some of those studies and also present in detail studies utilizing a promising, near-term, and practical source of cells for treatment of heart disease: autologous skeletal myoblasts.     

Evaluation of pituitary-thyroid axis response to acute myocardial infarction

We have studied with seriated controls for a period of 9 days 18 patients admitted to our hospital for acute myocardial infarction (AMI). Slight, but non significant variations in thyroidal hormone pattern were observed: slight decrease of T3 and T4 levels, increase of reverse T3 on day 3, low free T4 levels, slight increase of TSH levels until the 3rd day. However, hormonal pattern was clearly different in patients who presented a clinical improvement (group 1a) and in patients who died for AMI (group 1b). In fact, a significant TSH increase was recorded in patients of group 1a; on the contrary, a significant decrease of TSH, T4 and free T4 concentrations was observed for subjects of group 1b, suggesting an inadequate response of pituitary-thyroid axis. In conclusion, the evaluation of thyroid hormones and thyrotropin levels can be of clinical usefulness in the management of patients with AMI. The decrease of plasma T4 and free T4 concentrations, accompanied with low TSH levels, can be associated with unfavorable course of the disease and therefore can be considered a bad prognostic sign.     

Empowering adult stem cells for myocardial regeneration

Treatment strategies for heart failure remain a high priority for ongoing research due to the profound unmet need in clinical disease coupled with lack of significant translational progress. The underlying issue is the same whether the cause is acute damage, chronic stress from disease, or aging: progressive loss of functional cardiomyocytes and diminished hemodynamic output. To stave off cardiomyocyte losses, a number of strategic approaches have been embraced in recent years involving both molecular and cellular approaches to augment myocardial structure and performance. Resultant excitement surrounding regenerative medicine in the heart has been tempered by realizations that reparative processes in the heart are insufficient to restore damaged myocardium to normal functional capacity and that cellular cardiomyoplasty is hampered by poor survival, proliferation, engraftment, and differentiation of the donated population. To overcome these limitations, a combination of molecular and cellular approaches must be adopted involving use of genetic engineering to enhance resistance to cell death and increase regenerative capacity. This review highlights biological properties of approached to potentiate stem cell-mediated regeneration to promote enhanced myocardial regeneration, persistence of donated cells, and long-lasting tissue repair. Optimizing cell delivery and harnessing the power of survival signaling cascades for ex vivo genetic modification of stem cells before reintroduction into the patient will be critical to enhance the efficacy of cellular cardiomyoplasty. Once this goal is achieved, then cell-based therapy has great promise for treatment of heart failure to combat the loss of cardiac structure and function associated with acute damage, chronic disease, or aging.     

Autologous bone-marrow stem-cell transplantation for myocardial regeneration

Implantation of bone-marrow stem cells in the heart might be a new method to restore tissue viability after myocardial infarction. We injected up to 1.5x10(6) autologous AC133+ bone-marrow cells into the infarct border zone in six patients who had had a myocardial infarction and undergone coronary artery bypass grafting. 3-9 months after surgery, all patients were alive and well, global left-ventricular function was enhanced in four patients, and infarct tissue perfusion had improved strikingly in five patients. We believe that implantation of AC133+ stem cells to the heart is safe and might induce angiogenesis, thus improving perfusion of the infarcted myocardium. See Commentary page 11     

Role of stem cell homing in myocardial regeneration

Recent studies have demonstrated the potential for myocardial regeneration at the time of myocardial infarction. Our lab focuses on understanding how stem cells home to injured tissue. We believe that a detailed analysis of the biological responses to tissue injury not only gives us insight into how damage occurs, but can also yield insight into how the body attempts to repair itself. In the case of the heart, we have shown that these "healing pathways" are only expressed for a short time following injury, and this may be why myocardial damage is usually irreversible. Furthermore, work suggests that deciphering these "healing pathways" and re-establishing their expression at time remote from injury offers an avenue for developing novel therapeutics that ultimately may allow us to orchestrate and exaggerate the healing process at time remote from tissue injury.