Clinical calcium最新文献

The Wnt signaling pathway is known to play an important role in various biological processes including embryonic development and tissues homeostasis. Following the identification of the mutations in LRP5, encoding for the Wnt co-receptor low density lipoprotein receptor-related protein 5, associated with bone disorders in human, numerous studies have demonstrated the importance of Wnt signaling in bone cells. The Wnt signaling pathway is one of the key regulators of bone metabolism, hence the treatment using a monoclonal antibody against sclerostin, a bone-specific endogenous Wnt inhibitor, could improve bone mass and decrease fracture risk.

The Wnt signaling pathways are classified into the β-catenin dependent pathway, which regulates gene expression through β-catenin, and the β-catenin independent pathway, which does cytoskeletal rearrangement in a β-catenin independent manner. The former is also called as the canonical Wnt signaling pathway and extensively studied in development, tumorigenesis, and regenerative research. Recently, novel mechanistic insights into the canonical Wnt signaling pathway have been clarified through the analysis of structure of Wnt-receptor complex, regulation of Wnt signaling at the cell surface membrane, and intracellular protein complex of Wnt complexes.

The incidence of pregnancy complicated with renal dysfunction has tended to increase due to aging and progress in the treatment methods. Generally, pregnancy is allowed only in women with normal renal function and in patients with mild renal insufficiency; therefore, the incidence of osteoporosis and the resulting fragile fracture is rare during pregnancy complicated with renal dysfunction. In recent years, the incidence of pregnancy in dialysis patients and in patients who have undergone kidney transplantation has been increasing due to the progress in treatment methods. Eventually, it has become possible for patients with renal dysfunction to give birth as long as they fulfill certain conditions for pregnancy; however, the rate of preterm births has remained high. The incidence of femoral neck fracture has been about 5 times more in dialysis patients than in healthy individuals; however, the prevention and treatment of osteoporosis in pregnant dialysis patients have been difficult, since many osteoporosis medications are contraindicated in pregnant women and also their pregnancy period is not long due to the higher rate of preterm births.

To meet the fetus's calcium demand in the 3rd trimester as much as 300~500 mg/day, intestinal calcium absorption in pregnant women is upregulated, without comparable increase in bone resorption. On the contrary, to provide 210 mg/day of calcium for the neonate, bone resorption by osteoclasts and osteocytes is markedly upregulated in maternal skeleton caused by low estrogen and high PTHrP as a consequence of elevated prolactin production, without any increase in intestinal calcium absorption. Breastfeeding women lose 5~10%of trabecular bone during 3 to 6 months of lactation.

Post-pregnancy osteoporosis is a rare condition with little known pathophysiology. Most cases are diagnosed in the late stage of pregnancy or in the post partum while breastfeeding, particularly in first pregnancy. Non-traumatic vertebral fragility fractures are most commonly observed and characterized by prolonged severe pain and functional limitations. Conventional radiography will confirm the fracture in most cases, and magnetic resonance, which can be safely used during pregnancy, is effective in detecting vertebral fractures and bone marrow edema. It is important to exclude secondary osteoporosis, e.g. endocrine diseases, chronic liver and kidney diseases, autoimmune diseases, genetic diseases, drugs and malignant tumors. The prevalence of post-pregnancy osteoporosis is unknown, and may be estimated more than 3 for every ten thousand pregnant women. The pathophysiology of post-pregnancy osteoporosis is also unknown. The physiological bone resorption during reproduction does not normally cause fracture;instead, women who do fracture may be more likely to have additional secondary causes of bone loss and fragility, e.g. low body weight, low peak bone mass, malnutrition and heredity.

Diabetes mellitus causes hyperglycemia due to resistance to insulin action in peripheral organs in addition to progressive loss of β-cell function, thus it is involved in the development and progression of diabetic microangiopathy(retinopathy, nephropathy, and neuropathy). In addition, abnormalities of bone metabolism is regarded as a chronic complication related to both type 1 diabetes and type 2 diabetes. Accumulating evidence suggests that type 1 diabetes patients had decreased bone mineral density(BMD)and the fracture risk in the femoral neck is markedly higher, when compared to non-diabetic patients. A lack of insulin level in the portal vein is associated with systemic deficiencies of Insulin-like growth factor-1(IGF-1), known as growth-promoting polypeptide essential for promoting growth and bone formation. Thus, loss of IGF-1 play a crucial role for the pathogenesis of reduced BMD in type 1 diabetes. In type 2 diabetes, despite high bone mineral density with obesity, several studies have shown that men and women with type 2 diabetes mellitus are at increased risk for bone fracture. In other words, unlike type 1 diabetes patients, an increase in the risk of fracture in type 2 diabetes is significantly related to compromised bone quality, the other factor of impaired bone strength.

Cardiovascular disease(CVD)is a crucial cause of death in patients with chronic kidney disease and various factors play a role in the progression of CVD. Among the various factors, mineral bone disorder has been focused on in recent year. Phosphate is an important factor because it affects cardiovascular system not only directly but also indirectly. Phosphate can influence the serum and cellar levels of parathyroid hormone, fibroblast growth factor 23, and active vitamin D and thereby leading to the progression of CVD. Thus, it is essential to understand the mechanisms of CVD progression and think about a control of mineral bone disorder.

Intimal and medial calcification are increased with type 1 and type 2 diabetes, metabolic syndrome, chronic kidney disease, and ageing. There are several biological mechanisms through which vascular calcification increases all-cause mortality and atherosclerotic plaque rupture. Arterial medial calcification increases arterial stiffness that causes systolic hypertension and diastolic dysfunction and heart failure. In contrast, arterial intimal calcification is strongly associated with atherosclerotic plaque burden, predicting adverse arterial events. In particular, micro-calcifications within the fibrous caps are through to increase local stress and risk of plaque rupture. While vascular calcification has originally through to be a passive process, it has become increasingly clear that calcification of both intimal and medial layers is an active and tightly regulated process in which dynamic phenotypic changes of vascular smooth muscle cells plays a major role. Interestingly, the driving factors for medial and intimal calcification differ. Whilst uremia and senescence, high serum calcium and phosphate levels drives medial calcification, inflammation and oxidative stress are critical for intimal calcification. Despite the different drivers and environmental cues, the medial and intimal arterial calcification shares common intracellular signaling cascades to promoter cellular reprogramming and phenotypic switching. Recent studies employing new technologies demonstrate that calcifying extracellular vesicles(EVs)that have specific mineralization-promoting cargos such as tissue nonspecific alkaline phosphatase(TNAP), annexins Ⅱ and Ⅵ, are released from vascular smooth muscle, macrophages, and valvular interstitial cells, and serve as calcifying foci. Recent study identified a specific trafficking protein, sortilin, as a key player in the formation of calcifying EVs secreted by vascular smooth muscle cells. Research on aortic valve calcification using spatiotemporal multi-omics identified many secreted and structural matrix proteins not previously implicated in valvular calcification, and revealed that inflammation is likely to be a significant contributor regardless of the layers and stages of the aortic stenosis progression. Increased understanding of the precise molecular mechanisms of phenotypic switching of vascular smooth muscle offers the best chance to identify the potential drug targets for vascular calcification.

Growth spurts of the bone occur during infancy(1 to 4 years)and puberty(12 to 17 years). While, generally, pubertal spurts appear to draw more attention than infantile spurts, the latter constitute maximum growth spurts. Indeed, those during the first year of life lead to a 1.5-fold increase in height or a height increase of 25 cm, thus representing the greatest of all growth spurts that occur in humans during their lifetimes. Again, while height growth continues through the first 3 years of life, nutrition represents the single greatest contributing factor to height growth during this period. Again, while, as with other organ primordia, the bone primordium is formed during the organogenesis stage, calcification becomes most active during the third trimester of pregnancy. Thus, this review provides an overview of bone growth in humans, in relation to bone/calcium metabolism, which begins in the fetal stage before birth and continues through infancy and puberty, finally leading to attainment of peak bone mass in humans.

Multiple myeloma(MM)develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. A variety of cytokines are overproduced in MM to stimulate RANKL-mediated osteoclastogenesis while suppressing osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. Soluble Wnt inhibitors elaborated from MM cells and/or their surrounding cells in bone lesions play an important role. Novel therapeutic neutralizing antibodies against DKK-1 or sclerotin are expected as bone anabolic agents;however, their effects on MM tumor progression through activation of the Wnt/β-catenin pathway remain to be carefully clarified.