Alteration of proteoglycan sulfation affects bone growth and remodeling

Abstract

Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients. To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans.X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model.We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice. Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates. Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice. These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities.Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis.

Bone remodeling markers and bone metastases: From cancer research to clinical implications

“…[31][32][33][34][35][36][37][38][39][40][41] In addition, in nonhuman primate models, serum markers of bone resorption were also consistent with the observed phenotype. [42][43][44][45][46] Biomarkers of bone remodeling can also be used in in vitro models.…”

A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder

“…M aintaining the required biological ratio of sulfated versus non-sulfated molecules in the cell is critical for several biological processes ranging from fetal development and hormone metabolism to growth factor signalling, bone remodelling and degradation of macromolecules [1][2][3][4][5] . Thus, sulfate homeostasis is highly dynamic and tightly regulated by multiple enzymes including a large family of sulfatase enzymes that hydrolyse sulfate esters from many substrates, including sulfolipids, steroid sulfates and glycosaminoglycans (GAGs) 6 .…”

“…Sulfation represents an important protein modification, with diverse roles in several biological settings [1][2][3] . Importantly, sulfate metabolism is highly dynamic and sulfate groups are efficiently removed from sulfated proteins by a large family of sulfatase enzymes 7 .…”

A microscale bone remodeling simulation method considering the influence of medicine and the impact of strain on osteoblast cells

“…Then, a time step Δt n is determined based on the average single element resorption/formation period, as in Eq. (8). The microstructure configuration at time t n þ 1 ¼ Δt n þt n is updated.…”

“…Assuming the relationship between the density and elastic module, the density variation is calculated in accordance with the mechanical stimulus, which in this case, is the strain energy density. This method was frequently used to predict bone remodeling long after an orthopedic surgery [8,9] or implant [10][11][12]. Because the macroscale bone remodeling method only updated the density, it was incapable of simulating the morphological evolution of the bone structure.…”