Advances in Negative Regulatory Mechanisms of Sox9 Gene Expression during Cartilage Development

As the main regulator of cartilage development, Sox9 gene can initiate transcription and expression of various enzymes and protein genes required for car- tilage growth and development. During this process, the expression and function of Sex9 are also regulated by a variety of factors and signaling pathways. More re- search is concerned about the positive regulation. At present, some studies dis- closed that negative regulation of Sox9 expression existed unique mechanisms. This study will discuss and summarize the negative regulatory mechanism of Sox9 gene by microRNA, NF-κB, Wnt, Notch and other factors and signaling pathways, in or- der to provide the basic framework for further investigating the expression and func- tion of Sox9 in cartilage development.

Sox9a, not sox9b is required for normal cartilage development in zebrafish

Sox9 is a multifunctional gene and plays crucial roles in vertebrate development including chondrogensis.In teleost,due to the genome duplication event,there are two co-orthologs sox9a and sox9b.In this study,CRISPR/Cas9 technology was performed to disrupt the function of either sox9a or sox9b.All sox9a mutants(sox9aΔ10 and sox9aΔ67)and sox9b mutants(sox9bΔ11 and sox9bΔ20)lost HMG domain and Q/S domain,however,only sox9a mutant larvae had mis-shaped pectoral fins and lacked the scapulocoracoid cartilage.sox9b mutant larvae showed normal cartilages similar to wild type larvae.The results suggested that sox9a,not sox9b was required for cartilage development in zebrafish,which was different from the sox9b-mutant phenotype induced by N-ethyl-N-nitrosourea(ENU)treatment,gamma radiation treatment or morpholino injection.This study confirmed that ancestral sox9 gene functions partitioned between the two paralogs in zebrafish.

IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is crucial.The inositol-requiring enzyme 1a/X-box-binding protein-1 spliced(IRE1α/XBP1s)branch of the unfolded protein response(UPR)is essential for normal cartilage development.However,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains unknown.Herein,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates.Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.XBP1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage development.Meanwhile,ER stress cannot be activated normally in ERN1-deficient chondrocytes.In conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.ERN1 may have a potential role as a new target for cartilage growth and maturation.

Activation of the PGC-1α-mediated mitochondrial glutamine metabolism pathway attenuates female offspring osteoarthritis induced by prenatal excessive prednisone

Osteoarthritis is a chronic,age-related joint disease.Previous studies have shown that osteoarthritis develops during intrauterine development.Prednisone is frequently used to treat pregnancies complicated by autoimmune diseases.However,limited research has been conducted on the enduring effects of prednisone use during pregnancy on the offspring.In this study,we investigated the effect of excessive prednisone exposure on cartilage development and susceptibility to osteoarthritis in the offspring.We found that prenatal prednisone exposure(PPE)impaired cartilage extracellular matrix(ECM)synthesis,resulting in poor cartilage pathology in female offspring during the adult period,which was further exacerbated after long-distance running stimulation.Additionally,PPE suppressed cartilage development during the intrauterine period.Tracing back to the intrauterine period,we found that Pred,rather than prednisone,decreased glutamine metabolic flux,which resulted in increased oxidative stress,and decreased histone acetylation,and expression of cartilage phenotypic genes.Further,PGC-1α-mediated mitochondrial biogenesis,while PPE caused hypermethylation in the promoter region of PGC-1αand decreased its expression in fetal cartilage by activating the glucocorticoid receptor,resulting in a reduction of glutamine flux controlled by mitochondrial biogenesis.Additionally,overexpression of PGC-1α(either pharmacological or through lentiviral transfection)reversed PPEand Pred-induced cartilage ECM synthesis impairment.In summary,this study demonstrated that PPE causes chondrodysplasia in female offspring and increases their susceptibility to postnatal osteoarthritis.Hence,targeting PGC-1αearly on could be a potential intervention strategy for PPE-induced osteoarthritis susceptibility.