Zhang Xinli, Ting Kang, Pathmanathan Dharmini, Ko Theodore, Chen Weiwei, Chen Feng, Lee Haofu, James Aaron W, Siu Ronald K, Shen Jia, Culiat Cymbeline T, Soo Chia
Dental and Craniofacial Research Institute, Section of Orthodontics, School of Dentistry, UCLA and Orthopaedic Hospital Department of Orthopedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, California 90095, USA.
J Craniofac Surg. 2012 Jan;23(1):61-6. doi: 10.1097/SCS.0b013e318240c8c4.
Nell-1, first identified by its overexpression in synostotic cranial sutures, is a novel osteoinductive growth and differentiation factor. To further define Nell-1's role in craniofacial patterning, we characterized defects of the ENU-induced Nell-1-deficient (END) mice, focusing on both intramembranous and endochondral cranial bones. Results showed that calvarial bones of neonatal END mice were reduced in thickness and density, with a phenotype resembling calvarial cleidocraniodysplasia. In addition, a global reduction in osteoblast markers was observed, including reductions in Runx2, alkaline phosphatase, and osteocalcin. Remarkably, detailed analysis of endochondral bones showed dysplasia as well. The chondrocranium in the END mouse showed enrichment for early, proliferating Sox9⁺ chondrocytes, whereas in contrast markers of chondrocytes maturation were reduced. These data suggest that Nell-1 is an important growth factor for regulation of osteochondral differentiation, by regulating both Runx2 and Sox9 expression within the calvarium. In summary, Nell-1 is required for normal craniofacial membranous and endochondral skeletal development.
Nell-1最初是因其在颅骨缝早闭中过度表达而被发现的，是一种新型的骨诱导生长和分化因子。为了进一步明确Nell-1在颅面形态形成中的作用，我们对ENU诱导的Nell-1基因缺陷（END）小鼠的缺陷进行了表征，重点关注膜内成骨和软骨内成骨的颅骨。结果显示，新生END小鼠的颅骨厚度和密度降低，其表型类似于颅骨锁骨发育不全。此外，观察到成骨细胞标志物整体减少，包括Runx2、碱性磷酸酶和骨钙素的减少。值得注意的是，对软骨内骨的详细分析也显示发育异常。END小鼠的软骨颅显示早期增殖的Sox9⁺软骨细胞增多，而相比之下，软骨细胞成熟标志物减少。这些数据表明，Nell-1是通过调节颅盖骨内Runx2和Sox9的表达来调节骨软骨分化的重要生长因子。总之，Nell-1是正常颅面膜内和软骨内骨骼发育所必需的。
