Background and Objectives MAPK-activated protein kinase-2 (MK2) plays a key role in bone homeostasis. MK2 deficient mice have increased bone mineral density associated with reduced number of osteoclasts. Osteoclast differentiation is impaired due to reduced DNA binding activity of the transcription-factors c-fos and NFATc1. MK3 is besides MK2 an important downstream target of MAPK p38. MK3 plays together with MK2 an important role in regulation of cytokine secretion and inflammation. Aim of our study is to determine the role of MK3 and MK3/MK2 interaction in bone homeostasis.
Materials and Methods We analysed trabecular bone structure of the tibia of 12 week old wild type, MK3 deficient, MK2 deficient and MK2/3 deficient mice by micro CT. Tibiae were decalcified and paraffin sections were stained with tartrate-resistant acid phosphatase (TRAP) to determine osteoclast number/bone perimeter and osteoclast surface/bone surface by histomorphometry. Bone marrow cells of wild type, MK3 deficient, MK2 deficient and MK2/3 deficient mice were simulated with M-CSF and RANKL and stained for TRAP after four days to investigate osteoclast differentiation ex vivo.
Results Analysis of trabecular bone structure showed increased trabecular volume, increased trabecular number and decreased trabecular separation of MK3 deficient, MK2 deficient and MK2/3 deficient mice compared with wild type. MK3 deficient bones have lower trabecular number and higher trabecular separation than MK2 deficient bone while MK2/3 deficient bones showed the same phenotype than MK2 deficient bones. Number of osteoclasts was reduced in MK3 deficient, MK2 deficient and MK2/3 deficient bones in vivo compared with wild type. Number of osteoclasts was higher in MK3 deficient bones than in MK2 bones, MK2/3 deficient bones showed the same number of osteoclasts than MK2 deficient bones. Ex vivo osteoclast differentiation assay showed reduced osteoclasts number using MK3, MK2 and MK2/3 deficient cells compared with wild type cells.
Conclusions MK3 deficient mice showed increased trabecular bone volume than wild type mice, but trabecular volume was less increased than in MK2 deficient mice. MK2/3 deficient mice showed no additional effect compared to MK2 deficient mice. Increased trabecular volume was associated with reduced number of osteoclasts due to impaired osteoclast differentiation. Thus MK3 regulated osteoclast differentiation and bone homeostasis but there is no additional effect to MK2.
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