The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice

Abstract

Backgroundp38 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 FindingsWe 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.ConclusionsOur 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.

Focus on the p38 MAPK signaling pathway in bone development and maintenance

“…In addition to the clavicular and calvarial phenotypes, Tak1 mutant mice also exhibit reduced cortical and trabecular bone mass in limbs, and decreased mineralization of secondary ossification centers. 34 This global phenotype resembles that of Mkk3 À / À ; Mkk6 þ / À 34 and Osx-cre;p38alpha f/f mutant mice, 35 except that the clavicular hypoplasia is not seen in those mice, suggesting that another signaling pathway contributes to clavicle development. Pre-osteoblasts lacking TAK1 fail to differentiate into mature osteoblasts and have defective function.…”

“…34 The p38a MAPK represents the most abundant p38 member in bone, and its specific individual contribution in bone development and postnatal maintenance has been elucidated by using the Cre-LoxP technology. 35,36 Mice in which p38alpha is deleted under the control of the osterix (Osx) promoter exhibit impaired mineralization of frontal and parietal bones of the calvaria, delayed posterior fontanel ossification, and abnormal development of maxilla and mandible at birth, and decreased calvarial thickness, reduced trabecular bone volume and cortical thickness in long bones at 12 weeks of age, 35 which is in accordance with abnormal skeletal development of Mkk3 À / À and Mkk3 À / À ;Mkk6 þ / À mice. 34 Lack of p38a in pre-osteoblasts results in defective osteoblast differentiation, as evidenced by reduced expressions of Osx (encoding another master transcription factor regulating osteoblast p38 MAPK signaling in bone biology C Thouverey and J Caverzasio differentiation), collagen 1, alkaline phosphatase, bone sialoprotein and osteocalcin.…”

“…34 Lack of p38a in pre-osteoblasts results in defective osteoblast differentiation, as evidenced by reduced expressions of Osx (encoding another master transcription factor regulating osteoblast p38 MAPK signaling in bone biology C Thouverey and J Caverzasio differentiation), collagen 1, alkaline phosphatase, bone sialoprotein and osteocalcin. 35 Mice lacking p38a in mature osteoblasts (disruption under the control of the osteocalcin promoter) do not display bone alterations until 5 weeks of age, but then demonstrate a progressive decrease in bone mineral density and trabecular and cortical bone mass in both axial and appendicular skeletons. 36 Those abnormalities correlate with defective osteoblast function and impaired endosteal and trabecular bone formation.…”

“…36 Those data demonstrate the critical role of p38 MAPK in postnatal bone acquisition and remodeling, which has been also confirmed by the inducible ablation of p38alpha in pre-osteoblasts of adult mice. 35 In contrast, 4-month-old Mkk6 À / À mice, in which p38b cannot be activated, have normal osteoblast number and bone formation, 37 indicating that p38b does not have a significant role in adult bone homeostasis. Interestingly, absence of p38a in mature osteoblasts completely inhibits the bone anabolic effect of intermittent PTH treatment in mice, further supporting that p38a is an important component of PTH signaling in osteoblasts.…”

“…38 Disruption of either p38a or p38b MAPK signaling does not affect expressions of receptor activator of nuclear factor kappa-B ligand (Rankl) and osteoprotegerin, or bone resorption in physiological conditions. [34][35][36] Moreover, p38g expression is very low in osteoblasts, whereas p38d is expressed at the same level as p38a; 35,36 however, its role in osteoblast biology remains to be elucidated.…”