Exosomes: roles and therapeutic potential in osteoarthritis

Exosomes participate in many physiological and pathological processes by regulating cell–cell communication, which are involved in numerous diseases, including osteoarthritis(OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling.This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.

Inhibition of aberrant Hif1αactivation delays intervertebral disc degeneration in adult mice

The intervertebral disc(IVD) is the largest avascular tissue. Hypoxia-inducible factors(HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease(DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate(EP) and annulus fibrosus(AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol(2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

Clinical and genetic profiles of 985 Chinese families with skeletal dysplasia

To the Editor:Skeletal dysplasia is a group of clinical and genetic heterogeneous disorders with primary involvement of the musculoskeletal system,including bone,cartilage,tendons,ligaments,and muscles,and is usually characterized by short stature,motion limitation,or fragility fractures,sometimes complicated with extra-skeletal phenotypes.

Autophagy in the pathogenesis and therapeutic potential of post-traumatic osteoarthritis

Autophagy,as a fundamental mechanism for cellular homeostasis,is generally involved in the occurrence and progression of various diseases.Osteoarthritis(OA)is the most common muscu-loskeletal disease that often leads to pain,disability and economic loss in patients.Post-traumatic OA(PTOA)is a subtype of OA,accounting for>12%of the overall burden of OA.PTOA is often caused by joint injuries including anterior cruciate ligament rupture,meniscus tear and intra-articular fracture.Although a variety of methods have been developed to treat acute joint injury,the current measures have limited success in effectively reducing the incidence and delaying the progression of PTOA.Therefore,the pathogenesis and intervention strategy of PTOA need further study.In the past decade,the roles and mechanisms of autophagy in PTOA have aroused great interest in the field.It was revealed that autophagy could maintain the homeostasis of chondrocytes,reduce joint inflammatory level,prevent chondrocyte death and matrix degradation,which accordingly improved joint symptoms and delayed the progression of PTOA.Moreover,many strategies that target PTOA have been revealed to promote autophagy.In this review,we summarize the roles and mechanisms of autophagy in PTOA and the current strategies for PTOA treatment that depend on autophagy regulation,which may be beneficial for PTOA patients in the future.

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.

Total body water percentage and 3rd space water are novel risk factors for training-related lower extremity muscle injuries in young males

Purpose:To identify the risk factors for training-related lower extremity muscle injuries in young males by a non-invasive method of body composition analysis.Methods:A total of 282 healthy young male volunteers aged 18-20 years participated in this cohort study.Injury location,degree,and injury rate were adjusted by a questionnaire based on the overuse injury assessment methods used in epidemiological studies of sports injuries.The occurrence of training injuries is monitored and diagnosed by physicians and treated accordingly.The body composition was measured using the BodyStat QuadScan 4000 multifrequency Bio-impedance system at 5,50,100 and 200 kHz to obtain 4 impedance values.The Shapiro-Wilk test was used to check whether the data conformed to a normal distribution.Data of normal distribution were shown as mean±SD and analyzed by t-test,while those of non-normal distribution were shown as median(Q1,Q3)and analyzed by Wilcoxon rank sum test.The receiver operator characteristic curve and logistic regression analysis were performed to investigate risk factors for developing training-related lower extremity injuries and accuracy.Results:Among the 282 subjects,78(27.7%)developed training injuries.Lower extremity training injuries revealed the highest incidence,accounting for 23.4%(66 cases).These patients showed higher percentages of lean body mass(p=0.001),total body water(TBW,p=0.006),extracellular water(p=0.020)and intracellular water(p=0.010)as well as a larger ratio of basal metabolic rate/total weight(p=0.006),compared with those without lower extremity muscle injuries.On the contrary,the percentage of body fat(p=0.001)and body fat mass index(p=0.002)were lower.Logistic regression analysis showed that TBW percentage>65.35%(p=0.050,odds ratio=3.114)and 3rd space water>0.95%(p=0.045,odds ratio=2.342)were independent risk factors for lower extremity muscle injuries.Conclusion:TBW percentage and 3rd space water measured with bio-impedance method are potential risk factors for predicting the incidence of lower extremity muscle injuries in young males following training.

FGF/FGFR signaling in health and disease

Growing evidences suggest that the fibroblast growth factor/FGF receptor(FGF/FGFR)signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment,differentiation,proliferation,and apoptosis of various types of cells.In this review,we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development,injury repair,and the pathophysiology of spectrum of diseases,which is a consequence of FGF signaling dysregulation,including cancers and chronic kidney disease(CKD).In this context,the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.