Functional knockout of the matrilin-3 gene causes premature chondrocyte maturation to hypertrophy and increases bone mineral density and osteoarthritis
Functional knockout of the matrilin-3 gene causes premature chondrocyte maturation to hypertrophy and increases bone mineral density and osteoarthritis
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DOI：
10.2353/ajpath.2006.050981
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发表时间：
2006-08-01
影响因子：
6
通讯作者：
Chen, Qian
中科院分区：
文献类型：
--
作者：
van der Weyden, Louise;Wei, Lei;Chen, Qian
Matrlin-3(MATN3)是一种非胶原性细胞外基质蛋白，编码MATN3的基因突变在多种骨骼疾病中被报道，包括以骨痂不规则骨化和早发性骨关节炎为特征的多发性骨骺发育不良、脊柱-干骨干端发育不良和特发性手部骨关节炎。为了评估matrlin-3在这些疾病的发病机制中的作用，我们使用胚胎干细胞技术产生了Matn3功能敲除小鼠。在发育中的长骨的胚胎生长板中，Matn3缺失的软骨细胞过早肥大和肥大，形成肥大的扩张区。这种扩张在围产期减弱，Matn3纯合子缺失小鼠是存活的，出生时没有显示出严重的骨骼畸形。然而，到18周时，Matn3缺失小鼠的全身骨密度显著高于Matn1缺失小鼠或野生型小鼠。Matn3基因缺失的老年小鼠比它们的野生型小鼠更容易患上严重的骨关节炎。在这里，我们表明matrlin-3在胚胎发育过程中调节软骨细胞分化，在成年后控制骨密度，以及在衰老过程中预防骨关节炎方面发挥作用。缺乏Matn3不会导致出生后软骨发育不良，但会导致骨性关节炎的发生率更高。
Mutations in the gene encoding matrilin-3 (MATN3), a noncollagenous extracellular matrix protein, have been reported in a variety of skeletal diseases, including multiple epiphyseal dysplasia, which is characterized by irregular ossification of the epiphyses and early-onset osteoarthritis, spondylo-epimetaphyseal dysplasia, and idiopathic hand osteoarthritis. To assess the role of matrilin-3 in the pathogenesis of these diseases, we generated Matn3 functional knockout mice using embryonic stem cell technology. in the embryonic growth plate of the developing long bones, Matn3 null chondrocytes prematurely became prehypertrophic and hypertrophic, forming an expanded zone of hypertrophy. This expansion was attenuated during the perinatal period, and Matn3 homozygous null mice were viable and showed no gross skeletal malformations at birth. However, by 18 weeks of age, Matn3 null mice had a significantly higher total body bone mineral density than Matn1 null mice or wild-type littermates. Aged Matn3 null mice were much more predisposed to develop severe osteoarthritis than their wild-type littermates. Here, we show that matrilin-3 plays a role in modulating chondrocyte differentiation during embryonic development, in controlling bone mineral density in adulthood, and in preventing osteoarthritis during aging. The lack of Matn3 does not lead to postnatal chondrodysplasia but accounts for higher incidence of osteoarthritis.