Alteration of noncollagenous bone matrix proteins in distal renal tubular acidosis

Our previous report on bone histomorphometry in patients with distal renal tubular acidosis (dRTA) revealed decreased bone formation rate (BFR) when compared to healthy subjects. The abnormality improved significantly after alkaline therapy. The modest increase in osteoblastic surface, after correction of metabolic acidosis, could not explain the striking improvement in bone formation, suggesting additional influence of metabolic acidosis on osteoblast function and/or bone matrix mineralization. Osteoblasts and, to a lesser extent, osteoclasts synthesize and secrete bone matrix including type I collagen and various noncollagenous proteins (NCPs). Substantial evidence suggested diverse functions of NCPs related to bone formation, resorption, and mineralization. Metabolic acidosis, through its effect on bone cells, may result in an alteration in the production of NCPs. Our study examined bone histomorphometry with detailed analysis on the mineralization parameters and NCPs expression within the bone matrix of patients with dRTA before and after treatment with alkaline. Seven dRTA patients underwent bone biopsy at their initial diagnosis and again 12 months after alkaline therapy. Bone mineral density (BMD) and bone histomorphometry were obtained at baseline and after the treatment. The expression of NCPs was examined by immunohistochemistry, quantitated by digital image analysis, and reported as a percentage of area of positive staining or mineralized trabecular bone area. Alkaline therapy normalized the low serum phosphate and PTH during acidosis. The reduction in BMD at baseline improved significantly by the treatment. Bone histomorphometry demonstrated the increase in osteoid surface and volume without significant alteration after acidosis correction. In comparison to the normal subjects, osteoid thickness was slightly but insignificantly elevated. Osteoblast and osteoclast populations and their activities were suppressed. The reduction in mineral apposition rate and adjusted apposition rate were observed in conjunction with the prolongation of mineralization lag time. Alkaline therapy improved the mineralization parameters considerably. In addition to the increase in BFR relative osteoblast number after acidosis correction, osteocalcin expression in the bone matrix increased significantly from 16.7% to 22.3%. Six of seven patients had decreased osteopontin expression. In conclusion, the abnormal bone remodeling in dRTA is characterized by low turnover bone disease with some degree of defective mineralization. Alteration of NCPs expression suggested the effect of metabolic acidosis on bone cells. Alkaline therapy increased bone mass through the restoration of bone mineral balance and, perhaps, improved osteoblast function.     

Bullous pemphigoid and diabetes mellitus: a systematic review and meta-analysis

We aimed to systematically review and meta-analyze the association between diabetes mellitus (DM) and bullous pemphigoid (BP). Bullous pemphigoid (BP) is a prevalent autoimmune subepidermal blistering disease. Comorbid health conditions like neurological diseases and malignancies have been associated with BP. Growing evidence suggests that type 2 diabetes mellitus (T2DM) may increase the risk of developing BP. This review aims to synthesize this evidence. A systematic literature review was performed using Medline, PubMed, and Scopus in March 2022. Studies exploring the association between BP and DM were included. Data were extracted, and quality was assessed using the Newcastle–Ottawa scale. Meta-analysis was conducted to identify the odds ratio (OR) and 95% confidence intervals (CI) of the association. Seventeen studies were included, most being case–control studies from Europe and Asia. The pooled OR was 2.06 (95% CI: 1.61–2.62), suggesting a significant association between DM and BP. However, strong heterogeneity (I² = 88%) was observed. Evidence consolidates a significant relationship between DM and BP, potentially due to alterations in the immune system and skin properties caused by diabetes. Strengths of this review include a comprehensive search, rigorous methodology, large sample size, and heterogeneity evaluation. However, varying study quality, potential publication bias, and unaccounted confounding factors present limitations. There is a potential link between T2DM and an increased risk of BP. Further studies are required to understand this association and the underlying mechanisms.     

Vascular calcification in chronic kidney disease: Pathogenesis and clinical implication

Cardiovascular disease is the leading cause of death among patients with chronic kidney disease (CKD). Vascular calcification (VC) is one of the independent risk factors associated with cardiovascular disease and cardiovascular mortality in both the general population and CKD patients. Earlier evidence revealed substantially higher prevalence of VC in young adults on chronic hemodialysis compared to the general population in the same age range, indicating the influence of CKD-related risk factors on the development of VC. Pathogenesis of VC involves an active, highly organized cellular transformation of vascular smooth muscle cells to bone forming cells evidenced by the presence of bone matrix proteins in the calcified arterial wall. VC occurs in both the intima and the media of arterial wall with medial calcification being more prevalent in CKD. In addition to traditional cardiovascular risks, risk factors specific to CKD such as phosphate retention, excess of calcium, history of dialysis, active vitamin D therapy in high doses and deficiency of calcification inhibitors play important roles in promoting the development of VC. Non-contrast multi-slice computed tomography has often been used to detect coronary artery calcification. Simple plain radiographs of the lateral lumbar spine and pelvis can also detect VC in the abdominal aorta and femoral and iliac arteries. Currently, there is no specific therapy to reverse VC. Reduction of calcium load, lowering phosphate retention using non-calcium containing phosphate binders, and moderate doses of active vitamin D may attenuate progression. Parenteral sodium thiosulfate has also been shown to delay VC progression.     

Use of in vivo gene expression of isolated bone marrow mesenchymal stromal cells to study the pathophysiology of osteoporosis in patients with severe thalassemia

We compared osteoblast differentiation gene expressions in the isolated CD105 mesenchymal stromal cells from bone marrow in 10 patients with severe thalassemia and 12 normal donor controls. The fold expressions of osteoblast differentiation genes of CD105 cells from patients with thalassemia were lower than those of normal donors but increased after being cultured in Dulbecco's modified Eagle's medium with 10% fetal calf serum. Moreover, the fold expressions of these genes of CD105 cells from normal donors when cultured with 10% pooled serum of patients with thalassemia were lower than when cultured with 10% pooled serum of normal donors. We have also presented the evidence of reversible suppressed expression of these genes in CD105cells from patients with thalassemia when cultured in pooled serum of normal donors. Moreover, healthy donor CD105 cells exhibited lower expression of these genes when cultured in pooled serum of patients with thalassemia compared with pooled serum of normal donors indicating the existence of circulating factors in thalassemic serum impairing the differentiation of mesenchymal stromal cells to osteoblasts.