This Week in a Nutshell
Manesha Yadav, José Luis Millán, and colleagues, publishing in Bone, establish a dose-response relationship between ENB-0040 (previously known as sALP-FcD10) and repair of phenotypic traits of Akp2−/− mice (a model of hypophosphatasia which the group has previously established). Subcutaneous injections of ENB-0040 were strongly correlated with the prevention of mineralization defects and survival. The observed dose-response model observed suggests that a dosage of about 3.0 mg/kg/day prevents bone defects in approximately 80% of mice. Interestingly, the group observed that while urinary pyrophosphate levels are a good indicator of hypophosphatasia, they remain elevated even in the face of effective treatment. This suggests that urinary pyrophosphate levels will not be a helpful biomarker for assessing the success of treatment. Ultimately, this data helps establish therapeutic doses to be used in subsequent clinical trials of ENB-0040.
Samir M. Abdelmagid, Fayez F. Safadi, and colleagues, publishing in the Journal of Cellular Biochemistry, continue their work with osteoactivin (OA), a novel osteogenic factor. They assess the spatial and temporal distribution of osteoactivin and osteoactivin mRNA in intact tibia and in fracture calluses. They found OA localized in osteoblasts located in the metaphysis as well as in hypertrophic chondrocytes in the growth plate. Furthermore, they found elevated OA mRNA levels in fracture calluses as early as day 3 and extending to day 21 post fracture, with levels at day 5 (associated with chondrogenesis) significantly higher in the soft callus than in the intact femur. Finally, the continued presence of OA in newly formed collagen matrix and osteoid helps confirm OA's important role in bone formation and fracture repair.
Matthew D. Landrigan, Ryan K. Roeder, and colleagues, publishing in Bone, explore the use of contrast enhanced micro-CT in the three-dimensional characteristics of microcracks as an alternative to conventional histomorphometry methods. Using BaSO4 as a contrasting agent, they were able to visualize and quantify microdamage accumulation non-destructively in 3 dimensions. Microdamage accumulation was expressed as a ratio of total BaSO4 volume to total bone volume. Further investigation looks to address the lack of specificity and biocompatiblity of the BaSO4 contrast agent and to reduce the variability of the micro-CT data relative to the histomorphometry data. Ultimately, micro-CT measures of microdamage accumulation correlated well with corresponding histomorphometry data (p <0.05).
Julia Barsony, Joseph G. Verbalis, and colleagues, publishing in the Journal of Biological Chemistry, continue their work with chronic hyponatremia as a previously unrecognized cause of osteoporosis. Using an in vitro assay systems using preosteoclastic RAW 264.7 cells in one case and on primary bone marrow monocytes in another case, they demonstrated that lowering [Na+] concentrations in the culture medium increased osteoclast differentiation and resorption activity dose-dependently. Furthermore, restriction of ascorbic acid in the culture medium led to similar changes in differentiation and activity as well as indicators of hyponatremia-induced oxidative stress. Taken together these data indicate a novel sodium signaling mechanisms in osteoclasts that may prompt mobilization of sodium in bone stores during prolonged hyponatremia, thereby leading to a resorptive osteoporosis.