Molecular Mechanism Of Histone Demethylase KDM2B In Bone Mass Regulation

Osteoporosis is one of systemic bone diseases,which is characterized by the loss of bone mass,and the increase risk of bone fracture.Bone tissue is in a state of continuous remodeling,so as to maintain the stability of bone system.Bone remodeling is a dynamic process in which osteoclasts remove old or damaged bone by absorbing function,and then osteoblasts form new bone.When the abnormal activation of osteoclasts breaks the bone homeostasis,the rate of bone resorption is higher than that of bone formation,which leads to osteoporosis.The role of histone demethylase in bone homeostasis and osteoporosis risk has not been widely studied.KDM2B（also known as JHDM1B,FBXL10 or Ndy1）is the homolog to first identified histone demethylase KDM2A with Jmj C domain.A previous study reported that the spinal development of Kdm2b^{wt/ΔCxx C} mice is abnormal,which suggests that KDM2B may play an important role in the skeletal system.We speculated that KDM2B might play a regulatory role in bone remodeling.In order to explore the role of KDM2B in bone regulation,we first observed the phenotype of Kdm2b knockout mice.We found that the cancellous bone of femur in female Kdm2b knockout mice decreased significantly.The bone mass of cancellous in male Kdm2b knockout mice decreased but there was no statistical difference.The TRAP staining results of femur sections and skull showed that the osteoclast activity of the knockout mice was enhanced.Kdm2b knockout can promote osteoclast differentiation and inhibit the proliferation of osteoclast precursor cells.In addition,by ALP staining,Von Kossa staining and Alizarin Red staining,Kdm2b knockout can inhibit the differentiation and mineralization of osteoblasts in vitro.Goldner`s staining showed that the number,activity and osteoid secretion of osteoblasts decreased in Kdm2b^-/-female mice.The preliminary study on the molecular mechanism of KDM2B regulating osteoclast differentiation showed that KDM2B negatively regulates osteoclast differentiation depends on the Jmj C domain.Western blot experiments found that KDM2B does not affect the NF-κB signaling pathway,but affects osteoclast differentiation by inhibiting the expression and phosphorylation of ERK1.In conclusion,KDM2B can regulate osteoclast and osteoblast differentiation so as to affect bone mass.Our research provides new evidence for the regulation of epigenetic modifiers on osteoporosis,and also provides new ideas for the development of drug targets for the treatment of osteoporosis.