Future directions of molecular bone cell biology

Introduction of genetic approaches using knockout and/or transgenic mice has produced many pieces of information that can't be obtained by conventional cell biological studies and profoundly advanced our understanding of bone biology and metabolism. Here, the author will first briefly summarize the current findings in the recent bone research and subsequently attempt to predict future directions to which bone research is going to proceed with a special emphasis of osteoclast and osteoblast biology.     

Metabolic bone disease and bone quality

On the progress of study concerned with pathology of metabolic bone disease such as osteoporosis, it has been known that most of bone strength can be explained by bone volume. As bone volume can be determine by bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA), it has been widely used for diagnosis of osteoporosis or efficacy of treatment. However, with the advance of bone morphometry, decrease of bone strength or existence of insufficiency fracture is influenced by not only loss of BMD but also deterioration of bone quality especially bone microstructure. In this chapter, we will give an outline of change of bone quality in metabolic bone disease.     

Cell lines and primary cell cultures in the study of bone cell biology

Bone is a metabolically active and highly organized tissue consisting of a mineral phase of hydroxyapatite and amorphous calcium phosphate crystals deposited in an organic matrix. Bone has two main functions. It forms a rigid skeleton and has a central role in calcium and phosphate homeostasis. The major cell types of bone are osteoblasts, osteoclasts and chondrocytes. In the laboratory, primary cultures or cell lines established from each of these different cell types provide valuable information about the processes of skeletal development, bone formation and bone resorption, leading ultimately, to the formulation of new forms of treatment for common bone diseases such as osteoporosis.     

Metabolic bone disease

Metabolic bone dlseases are frequently seen in the geriatric population. The pain which often accompanies the disorder is a major cause of morbidity, frequent visits to the physician, health resource utilization, and even mortality. Successful prevention, detection and management of metabolic bone disease are essential components of optimal geriatric health care. This is the 4th paper presented in the symposium, Pathogenesis and Management of Pain in the Elderly, presented during the 16th Annual Meeting of AGE in Washington, D.C. on 9/25/86.     

Metabolic bone diseases

Osteomalacia is caused by impaired vitamin D receptor (VDR) signaling, calcium deficiency, and altered bone mineralization. This can be due to insufficient sunlight exposure, malabsorption, reduced D hormone activation in chronic kidney disease, and rare alterations of VDR signaling and phosphate metabolism. Leading symptoms are bone pain, muscular cramps, and increased incidence of falls in the elderly. The adequate respective countermeasures are to optimize the daily intake of calcium and vitamin D3 and to replace active D hormone and phosphate if deficient. Osteoporosis is characterized by bone fragility fractures upon minor physical impact. Indications for diagnosis and treatment can be established by estimating the absolute fracture risk, taking into account bone mineral density, age, gender, and individual risk factors. Exercise, intervention programs to avoid falls, and specific drugs are capable of substantially reducing fracture risk even in the elderly. Secondary osteoporosis primarily requires both bone-altering medications and effective treatment of underlying diseases.     

代谢性骨病与免疫

骨是参与钙磷代谢调节的主要器官,骨组织在一生中不断进行着新陈代谢,成骨细胞负责骨形成,破骨细胞负责骨吸收,使骨组织保持着骨转换的动态平衡。近期研究显示免疫调节因素可以活化破骨细胞,调节上述骨转换过程。许多免疫性疾病如类风湿性关节炎等均可伴有免疫系统激发的破骨细胞活化、骨吸收增强的全身性骨量减少。研究还发现,65岁以上的妇女骨密度降低与高的C反应蛋白(C Reactive Protein,CRP)水平相关[1],可见骨骼系统疾病与免疫系统联系密切,目前已出现了一个新的交叉学科-骨骼免疫学(Osteoimmunology)[2]。代谢性骨病是由于全身骨…     

Metabolic bone diseases and diabetes

Generalized osteoporosis, as one of the metabolic bone diseases, is often diagnosed in diabetics as late as after their first fracture. Alterations of bone metabolism should be therefore taken into account also in early stages of the basic disease. The risk of osteoporosis development is relatively high even in younger age groups of type 1 diabetics who suffer from defect of bone regeneration. In type 2 diabetics, the fractures are predominantly caused by more frequent falls and alterations of bone quality with normal or higher bone density. Therapy of osteoporosis in diabetics should include specific treatment regimes, supplementation with vitamin D and calcium, or an active antiosteoporotic therapy treating the basic disease.     

Metabolic bone disease and parenteral nutrition

Metabolic bone disease (MBD) is abnormal bone metabolism and includes the common disorders of osteoporosis and osteomalacia, which can develop in patients receiving longterm parenteral nutrition (PN). Patients who require longterm PN have significant gastrointestinal failure and malabsorption, which is generally caused by severe inflammatory bowel disease, intestinal ischemia, or malignancy. The exact cause of MBD in long-term PN patients is unknown, but its origin is thought to be multifactorial, with factors including underlying disease, effect of medications used to treat this disease (eg, corticosteroids), and various components of the PN solution. Caring for patients on long-term PN requires routine assessment and monitoring for MBD. Appropriate adjustments of the PN solution can help reduce the risk for developing PN-associated MBD and in some instances improve bone mineral density. Recent developments in pharmacologic treatment for osteoporosis show promise for patients with MBD receiving PN.     

Metabolic bone disease in IBD

A substantial number of patients with inflammatory bowel disease (IBD) will manifest extra-intestinal complications. Metabolic bone disease and arthropathies are among the most debilitating of these. Decreased bone mineral density and increased fracture risk may occur in relation to the underlying disease itself or result from vitamin, mineral, and hormonal deficiencies; medications used to treat the underlying disease; lifestyle; and perhaps other factors. In many cases, the factors remain unidentified. Options for the treating clinician include correction of these deficiencies, treatment of the underlying disease, and use of medication to promote bone formation and decrease bone resorption.     

Human bone marrow stromal cell: coexpression of markers specific for multiple mesenchymal cell lineages

The role of hematopoietic stem cells in blood cell development is reasonably understood, whereas the identity and the function of bone marrow stromal cells are much less clear. Using stromal cells in bone marrow cultures of the Dexter type, a favorite medium for the study of hematopoiesis, we show that stromal cells actually represent a unique cell type. Conventional wisdom has held that stromal cells in Dexter cultures comprise a mixture of macrophages, hematopoietic cells, adipocytes, osteoblasts, fibroblasts, muscle cells, and endothelial cells. Our findings demonstrate that Dexter cultures consist of three cell types: macrophages ( approximately 35%), hematopoietic cells ( approximately 5%), and nonhematopoietic cells ( approximately 60%). We have purified the nonhematopoietic cells free of macrophages and hematopoietic cells to produce compelling evidence that they in fact represent a single cell type (multidifferentiated mesenchymal progenitor cell, MPC) which coexpresses genes specific for various mesenchymal cell lineages including adipocytes, osteoblasts, fibroblasts, and muscle cells. We further show that these multi- or pluridifferentiated MPCs are capable of supporting hematopoiesis by demonstrating the expression of several hematopoietic growth factors and extracellular matrix receptors including G-CSF, SCF, VCAM-1, ICAM-1, and ALCAM. Since the MPCs can be easily purified to near homogeneity (95%), they can be of value in enhancing engraftment of hematopoietic stem cells. Also, this new understanding of bone marrow stromal cells as "one cell with many different faces" promises to advance our knowledge of regulatory cellular interactions within bone marrow.     

Metabolic bone disease after gastrectomy

An extensive survey revealed a significant biostatistical difference in the incidence of metabolic bone disease when 342 patients who had been treated with various types of partial gastrectomy were compared with a series of 180 patients with peptic ulcer of similar age and sex distribution. Thirty per cent of the postgastrectomy patients and only 5 per cent of the nonsurgical patients had defects in calcium metabolism.     

Metabolic markers of type I prediabetes]

Studies of the early metabolic alterations of type 1 diabetes aim at the quantification of the residual beta cell mass and its rate of destruction, as well as identifying predictive markers of insulin dependency. The first phase of insulin secretion during the intravenous glucose tolerance test has been mostly investigated. The test is satisfactorily reproducible provided it is standardized. The age and the insulin sensitivity of the subject should be taken into account when interpreting the results. Moreover, functional phenomenon that may be reversible may take part in the observed alterations of insulin secretion. The abolition of the first phase of insulin secretion always precedes insulin dependency, and has a good positive predictive value in subjects with anti-islet cell antibodies. However, some pre-diabetic subjects already have a low first phase insulin response from the first examination, which does not favour the hypothesis of a linear beta cell destruction and points to the heterogeneity of this stage of the disease. Conversely, profound metabolic alterations have been described with no progression towards insulin dependency, suggesting remission of the autoimmune process. The predictive value of the alterations of insulin secretion using other stimulus will be assessed by ongoing studies.     

Bone metastasis and bone metabolic markers

Bone metastasis is one of the major causes of morbidity for cancer patients. Recently, sensitive and specific bone metabolic markers have been identified and extensively examined in various bone diseases. In patients with bone metastasis, bone metabolic markers increased significantly and elevated further with the progression of bone metastasis. In conjunction with radiographic techniques, bone metabolic markers are useful in the diagnosis and the follow-up of bone metastasis.     

Bisphosphonate and markers for bone metabolism

Bisphosphonates (BPs) are widely applied to clinical use as first lines of therapeutic agents for metabolic bone diseases such as osteoporosis and Paget's disease of bone. Data on changes in markers for bone metabolism and their abilities to predict treatment efficacy have been accumulated in these bone disease and recently a guideline for adequate use of markers for metabolism in osteoporosis has been proposed. In the use of BPs, particularly ones containing amino residuals in their structures of side chains, attention should be paid to the choice of markers for bone metabolism since their degrees of changes depends on markers selected.