Trabecular bone deterioration in col9a1+/- mice associated with enlarged Osteoclasts adhered to collagen IX-deficient bone
Trabecular bone deterioration in col9a1+/- mice associated with enlarged Osteoclasts adhered to collagen IX-deficient bone
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DOI：
10.1359/jbmr.080214
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发表时间：
2008-06-01
影响因子：
6.2
通讯作者：
Nishimura, Ichiro
中科院分区：
文献类型：
--
作者：
Wang, Chiachien Jake;Iida, Keisuke;Nishimura, Ichiro
简介：短型胶原IX是成骨细胞表达的唯一同种型，通过col 9a 1基因的交替转录合成。短胶原IX在骨中的功能，其特征在于在col 9a 1-null mutant mice.Materials and Methods：骨小梁骨形态计量学的腰椎骨和胫骨进行了评价，通过mu CT和非脱钙组织学。成骨细胞和成骨细胞活性通过基于PCR和微阵列的基因表达测定和TRACP-5 b和C-末端肽（CTX）测定以及体外使用骨髓基质细胞和脾细胞进行评价。结果：Col 9a 1（+/-）基因敲除对小鼠骨骼发育无明显影响，但对成年雌性小鼠骨小梁有明显影响。随着年龄的增长，雄性和雌性杂合col 9a 1（+/-）小鼠的骨小梁结构逐渐恶化。老年突变小鼠也表现出胸椎后凸和体重减轻的迹象，类似于骨质疏松症的临床体征。col 9a 1（+/-）成骨细胞合成短col 9a 1转录物的速率降低。而骨形成活动在体外和体内不受影响，突变成骨细胞表达RANKL/骨保护素的比例升高。在col 9a 1（+/-）小鼠中发现血清TRACP-5 b和CTX水平升高，其骨表面与异常扁平和扩大的骨细胞相关。突变体和野生型脾细胞在体外经历了类似的破骨细胞生成;然而，RAW264.7衍生的破骨细胞在col 9a 1（+/-）颅骨上培养时，广泛分布在骨表面并形成大的吸收坑。col 9a 1（+/-）颅骨的表面被发现缺乏典型的nanotoptopics.Conclusions：矿化骨基质缺乏短胶原IX可能变得容易骨吸收，可能通过一种新的非细胞自主机制。这些数据表明骨胶原IX参与骨质疏松症的发病机制。
Introduction: Short collagen IX, the exclusive isoform expressed by osteoblasts, is synthesized through alternative transcription of the col9a1 gene. The function of short collagen IX in bone was characterized in col9a1-null mutant mice.Materials and Methods: Trabecular bone morphometry of lumbar bones and tibias was evaluated by mu CT and nondecalcified histology. Osteoblastic and osteoclastic activities were evaluated by PCR- and microarray-based gene expression assays and TRACP-5b and C-terminal telopeptide (CTX) assays, as well as in vitro using bone marrow stromal cells and splenocytes. The effect of col9a1(+/-) mutation on osteoclast morphology was evaluated using RAW264.7-derived osteoclastic cells cultured on the mutant or wildtype calvarial bone substrates.Results: Col9a1 knockout mutation caused little effects on the skeletal development; however, young adult female col9a1(-/-) and col9a1(+/-) mice exhibited significant loss of trabecular bone. The trabecular bone architecture was progressively deteriorated in both male and female heterozygous col9a1(+/-) mice while aging. The aged mutant mice also exhibited signs of thoracic kyphosis and weight loss, resembling the clinical signs of osteoporosis. The col9a1(+/-) osteoblasts synthesized short col9a1 transcripts at decreased rates. Whereas bone formation activities in vitro and in vivo were not affected, the mutant osteoblast expressed the elevated ratio of RANKL/osteoprotegerin. Increased serum TRACP-5b and CTX levels were found in col9a1(+/-) mice, whose bone surface was associated with osteoclastic cells that were abnormally flattened and enlarged. The mutant and wildtype splenocytes underwent similar osteoclastogenesis in vitro; however, RAW264.7-derived osteoclastic cells, when cultured on the col9a1(+/-) calvaria, widely spread over the bone surface and formed large resorption pits. The surface of col9a1(+/-) calvaria was found to lack the typical nanotopography.Conclusions: The mineralized bone matrix deficient of short collagen IX may become susceptible to osteoclastic bone resorption, possibly through a novel non-cell-autonomous mechanism. The data suggest the involvement of bone collagen IX in the pathogenesis of osteoporosis.