Gene therapy with serum calcium-decreasing factor, caldecrin, for osteoporosis

骨是一种动态组织，处于不断重塑或自我平衡的状态。这种重塑过程是成骨细胞和破骨细胞活动之间的平衡。干扰这种平衡会导致骨质疏松症。单核细胞/巨噬细胞谱系的破骨细胞分化受到局部因素的影响。RANKL/ODF/OPGL对破骨细胞的形成至关重要。血清降钙因子钙脱蛋白是一种新型丝氨酸蛋白酶，它在没有蛋白酶活性的情况下抑制成熟破骨细胞骨吸收。RANKL或TNF-α刺激小鼠骨髓源性破骨细胞前体细胞分化。为了确定钙脱蛋白是否是骨质疏松形成的有效抑制剂，我们首先评估了钙脱蛋白对RANKL或TNF-α刺激的破骨细胞生成的影响。钙降蛋白抑制小鼠体外破骨细胞生成。钙decrin抑制RANKL处理后NFATc1 mRNA的升高。因此，钙脱蛋白以未知的机制抑制成熟破骨细胞功能和破骨细胞生成。接下来，我们评估了小鼠股骨肌钙脱蛋白基因表达对雌激素缺乏引起的骨质流失的影响。8周龄时分别假手术或去卵巢，在肌肉中表达大鼠钙蛋白基因2周。钙脱蛋白表达小鼠血清钙和胶原c肽浓度降低。组织学分析显示，OVX组股骨远端松质骨的骨体积和骨小梁厚度明显降低，并通过钙脱蛋白基因表达恢复。这些结果表明钙钙蛋白是一种有效的骨质疏松症抑制剂。

Bone is a dynamic tissue that is under a constant state of remodeling or homeostasis. This remodeling process is a balance between the activities of osteoblasts and osteoclasts. Interference with this balance causes osteoporosis. Osteoclast differentiation from the monocyte/macrophage lineage is influenced by local factors. RANKL/ODF/OPGL is essential for osteoclastgenesis. Serum calcium-decreasing factor, caldecrin, is a novel serine protease and suppresses matured osteoclastic bone-resorption without the protease activity. Differentiation of mouse bone-marrow derived osteoclast precursor cells was stimulated by RANKL or TNF-α. To determine whether caldecrin is potent inhibitor of osteoporosis processing, we first evaluated the effect of caldecrin on the RANKL or TNF-α stimulated osteoclastgenesis. Caldecrin suppressed mouse in vitro osteoclastgenesis. Caldecrin suppressed the increase of NFATc1 mRNA after treatment with RANKL. Thus, caldecrin suppresses mature osteoclast function and osteoclastgenesis by unknown mechanism. Next, we evaluated the effect of caldecrin gene expression in the mouse femoris muscle on the estrogen deficiency induced bone loss. At 8 weeks of age mice were either sham operated or ovariectomized, and rat caldecrin gene was expressed in the muscle for 2 weeks. The concentration of serum calcium and collagen C-peptide was decreased in the caldecrin expressed mice. Histological analysis showed that bone volume and trabecular thickness in the distal femoral cancellous bone were significantly lower in the OVX, and restored by the caldecrin gene expression. These results suggest that caldecrin is a potent inhibitor of osteoporosis.