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Osteoarthritis (OA) is one of the most prevalent skeletal diseases. Recently, we identified a novel gene on chromosome 3p24.3, named DVWA (double von Willebrand factor A domains), and its functional variants, which are associated with susceptibility to knee OA. Here we report the cloning and characterization of the DVWA gene. DVWA consisted of seven exons and had four alternative splicing variants, which encoded long (385 amino acid) and short (276 amino acid) proteins (L-DVWA and S-DVWA, respectively). S-DVWA was an N-terminal truncated form of L-DVWA and lacked a signal peptide and a part of a VWA domain. L-DVWA and S-DVWA transcripts were mainly expressed in articular cartilage. Immunoblot analysis using epitope-tagged proteins showed L-DVWA in the conditioned media and S-DVWA only in the cell, consistent with the in silico prediction. We also cloned the murine counterpart of DVWA, which was found to be identical to Col6a4, which has recently been reported. L-DVWA had 73% identity to the N-terminal sequence of the 2,309-amino acid Col6a4 protein. The mouse Dvwa/Col6a4 mRNA was present mainly in the small intestine in embryos and adults, but not in cartilage. The amino acid sequence of L-DVWA was conserved in higher species than chicken, but that of S-DVWA was unique in human. Knockdown of DVWA by siRNAs increased expression of chondrocyte matrix genes. Our study indicates that DVWA is evolutionally very unique, which, together with its specific expression in articular cartilage, suggests its specific role in human cartilage metabolism.

Reference values of bone mineral density (BMD) have mainly been based on hospital volunteers in Japan. Consequently, these values may be inappropriate for the use as a standard in the osteoporotic study. In order to establish reference values, BMD was measured of 400 age-stratified inhabitants of Miyama Village, utilizing dual energy x-ray absorptiometry (DEXA). The mean BMD of L2–L4 in males in each age group was 1.19±0.16 g/cm2 (mean±standard deviation) in 40's, 1.15±0.19 g/cm2 in 50's, 1.03±0.18 g/cm2 in 60's and 1.06±0.25 g/cm2 in 70's. The difference of BMD was statistically significant between the 50 and 60 age groups. On the other hand, in females the mean BMD of L2–L4 was 1.18±0.16 g/cm2 in 40's; 0.99±0.18 g/cm2 in 50's, 0.84±0.19 g/cm2 in 60's and 0.78±0.17 g/cm2 in 70's. The BMD was significantly lower in the 50 age group than in the 40 age group and was similarly lower in the 60 age group than in the 50 age group. The mean BMD of femoral neck in males was 0.98±0.14 g/cm2 in 40's, 0.91±0.12 g/cm2 in 50's, 0.83±0.11 g/cm2 in 60's and 0.78±0.11 g/cm2 in 70's. In females, the BMD of femoral neck was 0.88±0.11 g/cm2 in 40's, 0.75±0.11 g/cm2 in 50's, 0.68±0.11 g/cm2 in 60's and 0.63±0.10 g/cm2 in 70's. BMD of the femoral neck in an older age group was lower than that in a younger age group both in males and females.

Rat osteocalcin was subjected to proteolysis by cathepsins B and L at acid pH in vitro. Short fragments of fewer than 8 amino acids were liberated from both the NH2- and COOH-termini of the molecule, but the midportion, composed of antiparallel α-helical domains, was resistant to proteolysis. Intact rat osteocalcin bound 10 Ca2+/mol protein at pH 7.5 and the binding decreased to half that amount at pH 5.0, while the midportion fragment (Ala8-Lys43) bound 4–5 Ca2+/mol protein at both pH 5.0 and 7.5. When COOH-terminal-truncated rat osteocalcin (Tyr1-Lys43) was prepared with lysyl-endopeptidase, it showed nearly the same Ca2+ binding as that of the intact molecule. Our results suggest that proteolytic processing of the terminal sequence of osteocalcin alters its intrinsic Ca2+-binding capacity and that its NH2-terminal sequence is probably involved.

Calcium homeostasis plays vital roles in the management of bone health. Traditional herbal formula Gushukang (GSK) was clinically applied to treat primary osteoporosis. This study aimed to explore the osteoprotective effects of GSK and its roles in maintaining calcium homeostasis in ovariectomized (OVX) mice. The OVX mice were orally treated with low (0.38 g/kg), middle (0.76 g/kg) and high (1.52 g/kg) dose of GSK for 8 weeks. GSK treatment dramatically increased serum calcium level and decreased urinary calcium excretion as well as enhanced calcium content in bone of OVX mice. Serum level of 25-hydroxyvitamin D was significantly increased in OVX mice with exposure to GSK. Treatment with GSK improved bone mass and micro-structure of trabecular bone at distal metaphysis of femur and proximal metaphysis of tibia in OVX mice shown by safranin O staining and micro-CT measurement. GSK treatment at all doses up-regulated mRNA expression of calcium-binding protein-28k and vitamin D receptor in kidney of OVX mice, and dose-dependently decreased mRNA expression of claudin-14 and elevated mRNA expression of claudin-16 in duodenum of OVX mice. Taken together, GSK exerted beneficial effects on trabecular bone of OVX mice by improving calcium homeostasis via regulating paracellular calcium absorption in duodenum and transcellular calcium reabsorption in kidney.

With the acceleration of population aging, the incidence of osteoporosis has gradually increased, and osteoporosis and fractures caused by osteoporosis have gradually become a serious social public health problem. The classic role of the renin–angiotensin–aldosterone system (RAAS) is to keep blood pressure stable. However, as the components of RAAS were found in bone tissues, their functions of stimulating osteoclast formation and inhibiting osteoblast activity thus inducing bone loss have gradually emerged. RAAS blockers can prevent osteoporotic fractures which may be related to angiotensin type 1 (AT1) receptor, osteoprotegerin (OPG)/nuclear factor-κB ligand (RANKL), and angiotensin-converting enzyme 2 (ACE2)/angiotensin (1–7) (Ang (1–7))/G protein-coupled receptor (Mas) cascade. However, some studies suggest that RAAS blockers do not prevent osteoporotic fractures. This article reviews the effects of RAAS and RAAS inhibitors on bone metabolism and provides new ideas for the prevention of osteoporosis.

Osteoporosis has become a worldwide public health problem, in part due to the fact that it increases the risk of fragility hip fractures (FHFs). The epidemiological assessment of FHFs is critical for their prevention; however, datasets for FHFs in Japan remain scarce. This was a multicenter, prospective, observational study in the northern district of Kyushu Island. Inclusion criteria were age > 60 years with a diagnosis of FHF and acquisition of clinical data by an electronic data capture system. Of 1294 registered patients, 1146 enrolled in the study. Nearly one third of patients (31.8%) had a history of previous fragility fractures. The percentage of patients receiving osteoporosis treatment on admission was 21.5%. Almost all patients underwent surgical treatment (99.1%), though fewer than 30% had surgery within 48 h after hospitalization. Bone mineral density (BMD) was evaluated during hospitalization in only 50.4% of patients. The rate of osteoporosis treatment increased from 21.5% on admission to 39.3% during hospitalization. The main reasons that prescribers did not administer osteoporosis treatment during hospitalization were forgetfulness (28.4%) and clinical judgment (13.6%). Age and female ratio were significantly higher in patients with previous FHFs than in those without. There was a significant difference in the rate of osteoporosis treatment or L-spine BMD values in patients with or without previous FHFs on admission. In conclusion, this study confirmed that the evaluation and treatment of osteoporosis and FHFs is still suboptimal in Japan, even in urban districts.