Mechanism Of GPR35 Regulating Bone Remodeling

Osteoporosis is characterized by reduced bone mass,destroyed bone tissue structure,resulting in decreased bone structure,increased bone fragility and increased fracture probability.While osteoporosis-induced pain is one of the most prone to chronic pain associated with neurological disorders.Causes of osteoporosis and pain can be explained by the dynamic balance of bone remodeling is destroyed.Osteoclast abnormal activation leads to accelerated bone resorption rate and sharp erosion of old bone.Too much H + released from this process acidified bone microenvironment and activates both types of pain receptors TRPV1 and ASIC-3,passing pain signals to the brain through the dorsal root ganglion(DRG)to cause pain.Most of today’s best-selling drugs for the treatment of osteoporosis are by inhibiting osteoclast activity to achieve treatment,in another important part of bone remodeling balance—osteoblast bone formation is not fully considered,osteoporosis caused by the pain is not alleviated or even there are many side effects.GPR35 has a higher level of expression in the immune system,the skeletal system,dorsal root ganglion,and is reported to be mediated by TRPV1-mediated inflammatory acidic conditions.We hypothesize that GPR35 may play an important regulatory role in bone remodeling and pain caused by osteoporosis.In this study,we found that activation of GPR35 by agonists in vitro can inhibit osteoclast differentiation and promote osteoblast differentiation in vitro.The absence of GPR35 has no significant effect on the proliferation of osteoclast precursor cells,but can enhance osteoclast differentiation,prolong the survival time of mature osteoclasts,promote the formation and fusion of osteoclasts,increase bone resorption rate and inhibit mesenchymal stem cells Proliferation,osteoblast differentiation,mineralization.In vivo studies have shown that knockout of GPR35 leads to an increase in osteoclast activity,an increase in the number of osteoblasts,activity and bone formation rates in the body,and a decrease in bone tissue intensity,resulting in an overall decrease in bone mass and bone mass.In the ovariectomized simulated osteoporotic pathology conditions,knockout GPR35 can lead to more severe bone loss.In addition,the expression of TRPV1 and ASIC-3 in GPR35 knockout mice was significantly higher than that in WT mice under the pathological conditions caused by ovariectomy.A preliminary study of the intracellular molecular mechanism of GPR35-regulated bone remodeling suggests that negative regulation of osteoclast activity by GPR35 may be mediated by inhibition of phosphorylation of p65 and inhibition of IκKα degradation and positive regulation of osteoblast activity by enhancing Wnt/β-Catenin signal and a significant increase of RUNX2.In summary,GPR35 has the potential to become a new drug target for the treatment of osteoporosis while relieving pain caused by osteoporosis.