Rodríguez-Carballo Edgardo, Gámez Beatriz, Sedó-Cabezón Lara, Sánchez-Feutrie Manuela, Zorzano Antonio, Manzanares-Céspedes Cristina, Rosa José Luis, Ventura Francesc
Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
PLoS One. 2014 Jul 9;9(7):e102032. doi: 10.1371/journal.pone.0102032. eCollection 2014.
p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified.
METHODOLOGY/PRINCIPAL FINDINGS: We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months.
Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.
p38丝裂原活化蛋白激酶（MAPK）活性通过激活成骨细胞特异性转录因子，在成骨细胞谱系进展的多个步骤中发挥重要作用，并且对于早期发育过程中成骨细胞表型的获得也至关重要。尽管有报道表明p38信号通路在早期骨骼发育中起作用，但其对成年骨重塑的具体贡献仍有待阐明。
方法/主要发现：我们评估了成骨细胞特异性敲除p38α，以确定其在早期骨骼发生以及成年骨骼骨稳态中的意义。早期敲除p38α导致颅骨和长骨的膜内成骨和软骨内成骨出现缺陷。突变小鼠股骨远端的小梁骨体积减少，伴有小梁厚度降低。此外，基因敲除小鼠的股骨皮质骨体积和厚度也降低。敲除p38α不影响破骨细胞功能。然而，它通过降低成骨细胞特异性转录因子及其靶标的表达，损害了成骨细胞生成、成骨细胞成熟和活性。此外，诱导型Cre系统使我们能够通过去除强力霉素来控制出生后p38α破坏的起始时间。出生后三周或八周敲除p38α，在6或12个月后导致小梁骨和皮质骨体积显著降低。
我们的数据表明，除了早期骨骼发生外，p38α对于成骨细胞在矿化的成年骨骼中维持其功能至关重要，因为骨合成代谢应在整个生命过程中持续进行。此外，我们的数据还强调，p38抑制剂的临床开发应考虑其潜在的骨骼效应。
