کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2779167 1568147 2015 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شناسی تکاملی
پیش نمایش صفحه اول مقاله
Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio
چکیده انگلیسی


• Abnormal bone phenotypes in thrombin receptor knockout (TR KO) mice are proposed.
• Cortical bone volume and polar moment of inertia are enhanced in TR KO group.
• Trabecular thickness and connectivity are increased in TR KO group.
• Thrombin and TR regulate RANKL/OPG synthesis through the p42/44-ERK pathway.

Thrombin and its receptor (TR) are, respectively, expressed in osteoclasts and osteoblasts. However, their physiological roles on bone metabolism have not been fully elucidated. Here we investigated the bone microarchitecture by micro-computed tomography (μCT) and demonstrated increased trabecular and cortical bone mass in femurs of TR KO mice compared to WT littermates. Trabecular thickness and connectivity were significantly enhanced. The physiological role of TR on both inorganic and organic phases of bone is illustrated by a significant increase in BMD and a decrease in urinary deoxypyridinoline (DPD) crosslink concentration in TR KO mice. Moreover, TR KO cortical bone expanded and had a higher polar moment of inertia (J), implying stronger bone. Bone histomorphometry illustrated unaltered osteoblast and osteoclast number and surface in femoral metaphyses, indicating that thrombin/TR regulates osteoblasts and osteoclasts at functional levels. Serum analysis showed a decrease in RANKL and an increase in osteoprotegerin (OPG) levels and reflected a reduced RANKL/OPG ratio in the TR KO group. In vitro experiments using MC3T3 pre-osteoblasts demonstrated a TR-dependent stimulatory effect of thrombin on the RANKL/OPG ratio. This effect was blocked by TR antagonist and p42/p44-ERK inhibitor. In addition, thrombin also intensified p42/p44-ERK expression and phosphorylation. In conclusion, the thrombin/TR system maintains normal bone remodeling by activating RANKL and limiting OPG synthesis by osteoblasts through the p42/44-ERK signaling pathway. Consequently, TR deficiency inhibits osteoclastogenesis, resulting in a high bone mass phenotype.

Figure optionsDownload high-quality image (332 K)Download as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bone - Volume 72, March 2015, Pages 14–22
نویسندگان
, , , , , , ,