Mechanisms of action of neuropeptide Y on stem cells and its potential applications in orthopaedic disorders

Musculoskeletal disorders are the leading causes of disability and result in reduced quality of life.The neuro-osteogenic network is one of the most promising fields in orthopaedic research.Neuropeptide Y(NPY)system has been reported to be involved in the regulations of bone metabolism and homeostasis,which also provide feedback to the central NPY system via NPY receptors.Currently,potential roles of peripheral NPY in bone metabolism remain unclear.Growing evidence suggests that NPY can regulate biological actions of bone marrow mesenchymal stem cells,hematopoietic stem cells,endothelial cells,and chondrocytes via a local autocrine or paracrine manner by different NPY receptors.The regulative activities of NPY may be achieved through the plasticity of NPY receptors,and interactions among the targeted cells as well.In general,NPY can influence proliferation,apoptosis,differentiation,migration,mobilization,and cytokine secretion of different types of cells,and play crucial roles in the development of bone delayed/non-union,osteoporosis,and osteoarthritis.Further basic research should clarify detailed mechanisms of action of NPY on stem cells,and clinical investigations are also necessary to comprehensively evaluate potential applications of NPY and its receptor-targeted drugs in management of musculoskeletal disorders.

Stimulating factors for regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells

Mesenchymal stem cells(MSCs),distributed in many tissues in the human body,are multipotent cells capable of differentiating in specific directions.It is usually considered that the differentiation process of MSCs depends on specialized external stimulating factors,including cell signaling pathways,cytokines,and other physical stimuli.Recent findings have revealed other underrated roles in the differentiation process of MSCs,such as material morphology and exosomes.Although relevant achievements have substantially advanced the applicability of MSCs,some of these regulatory mechanisms still need to be better understood.Moreover,limitations such as long-term survival in vivo hinder the clinical application of MSCs therapy.This review article summarizes current knowledge regarding the differentiation patterns of MSCs under specific stimulating factors.

Ten years of hip fractures in Italy: For the first time a decreasing trend in elderly women

AIM:To evaluate the hospitalization rate of femoralneck fractures in the elderly Italian population over ten years.METHODS:We analyzed national hospitalizations records collected at central level by the Ministry of Health from 2000 to 2009.Age-and sex-specific rates of fractures occurred at femoral neck in people≥65 years old.We performed a sub-analysis over a three-year period(2007-2009),presenting data per five-year age groups,in order to evaluate the incidence of the hip fracture in the oldest population.RESULTS:We estimated a total of 839008 hospitalizations due to femoral neck fractures between 2000 and2009 in people≥65,with an overall increase of 29.8%over 10 years.The incidence per 10000 inhabitants remarkably increased in people≥75,passing from158.5 to 166.8(+5.2%)and from 72.6 to 77.5(+6.8%)over the ten-year period in women and men,respectively.The oldest age group(people>85 years old)accounted for more than 42%of total hospital admissions in 2009(n=39000),despite representing only 2.5%of the Italian population.Particularly,women aged>85accounted for 30.8%of total fractures,although they represented just 1.8%of the general population.The results of this analysis indicate that the incidence of hip fractures progressively increased from 2000 to 2009,but a reduction can be observed for the first time in women≤75(-7.9%between 2004 and 2009).CONCLUSION:Incidence of hip fractures in Italy are continuously increasing,although women aged 65-74years old started showing a decreasing trend.

Role of biomechanical assessment in rotator cuff tear repair: Arthroscopic vs mini-open approach

BACKGROUND Rotator cuff(RC)tears are one of the most frequent pathologies within the shoulder girdle.Hand dominance and older age are associated with RC tears.Two different surgical procedures,the mini-open(MO)and all-arthroscopic(AA)approach,represented the standard of treatment.AIM To compare the clinical and biomechanical outcomes of two surgical techniques(AA vs MO procedure)performed to address the painful shoulder syndrome with partial or total supraspinatus tendon tear.METHODS Eighty-eight participants,50 following RC repair with AA and 38 with MO approach,were recruited in the present cross-sectional case-control study(ORTHO-SHOULDER,Prot.0054602).All patients underwent postoperative clinical evaluation for pain(Visual analogic scale),impairment,and disability(disability of the arm,shoulder,and hand)and limitation in daily activity(Constant-Murley score).Patients’shoulder mobility was also assessed in our Laboratory of Functional Movement through a wearable inertial sensor and surface electromyography to monitor kinematics and muscle activity during the movement on the frontal(abduction/adduction)and sagittal(flexion-extension)planes.RESULTS No statistically significant differences between the two procedures were observed in either main clinical score or range of motion.A significant increase in velocity during the movement execution and a higher contribution of upper trapezius muscles were found in the AA group compared with MO patients.CONCLUSION In terms of clinical scores,our findings were in line with previous results.However,the use of technology-based assessment of shoulder mobility has revealed significant differences between the two techniques in terms of mean velocity and pattern of muscle activation.

Role of lateral soft tissues release in percutaneous hallux valgus correction:A medium term retrospective study

BACKGROUND In the field of minimally invasive surgery(MIS)for the treatment of hallux valgus(HV),different techniques have begun to emerge in the literature concerning the distal osteotomy of the first metatarsal bone,the synthesis or not of the metatarsal head,the possible association with lateral soft tissues release(LSTR)and osteotomy of the base of the first phalanx.AIM To evaluate the role of LSTR on percutaneous HV correction,evaluating functional and radiographical results.METHODS From January 2012 to May 2016 a total of 396 patients with mild to moderate symptomatic HV treated with the MIS technique were included in this retrospective study.The technique provides no internal fixation(WOS).Patients were divided into the LSTR group and no LSTR group(LSTR N).This surgical procedure(LSTR)was reserved for insufficient HV angle(HVA)correction during fluoroscopic control.Patients were evaluated at each follow-up by two other authors after appropriate training by senior authors(first practitioners).Clinical evaluation was performed before surgery,6 mo after surgery,and 48 mo follow-up.American Orthopaedic Foot and Ankle Society(AOFAS)and visual analog scale(VAS)score was used to evaluate pain and function,and complications were recorded.In addition,the incidence of relapses and the degree of joint range of motion(ROM)with the association with the LSTR(capsule,adductor tendon,phalanx-sesamoid ligament,and the deep transverse metatarsal ligament)were evaluated.Radiological parameters included HVA and intermetatarsal angle(IMA).Patient satisfaction was assessed.Student t-test and Fisher exact test were used to assess statistical analysis.RESULTS From our study it is clear that no differences in term of HVA,VAS,IMA correction,rate of complications,and AOFAS score were found between groups,while a significant improvement of the same variables was found in each group between pre and postoperative values.A significant improvement in ROM at 6 mo(P=0.018)and 48 mo(P=0.02)of follow-up was found in LSTR N group.Complications were rare in both groups.CONCLUSION LSTR procedure on percutaneous HV correction seems to increase postoperative joint stiffness with a comparable incidence of relapse and a low incidence of complications.

TREATMENT OF 104 CASES SUFFERING FROM CERVICO-SPINAL HYPERTENSION WITH ROTATION-REDUCTION METHOD——Observation of the Long-Term Effect

Since 1976,the authors began to carry outclinical research work on the treatment of blooddisorders(hypertension and hypotension)due tocervico-spinal diseases with the rotation-reductionmethod.A preliminary analysis and summarywere made,and the achievements of this scien-tific research passed technological appraisal inJune,1983.In recent years,the authors havemade an observation of the long-term effect of thetreatment of cervico-spinal hypertension with thismethod,with satisfactory results,which will bereported as follows.

Single nucleotide variations in the development of diabetic foot ulcer: A narrative review

Diabetes mellitus has become a global health problem,and the number of patients with diabetic foot ulcers(DFU)is rapidly increasing.Currently,DFU still poses great challenges to physicians,as the treatment is complex,with high risks of infection,recurrence,limb amputation,and even death.Therefore,a comprehensive understanding of DFU pathogenesis is of great importance.In this review,we summarized recent findings regarding the DFU development from the perspective of single-nucleotide variations(SNVs).Studies have shown that SNVs located in the genes encoding C-reactive protein,interleukin-6,tumor necrosis factor-alpha,stromal cell-derived factor-1,vascular endothelial growth factor,nuclear factor erythroid-2-related factor 2,sirtuin 1,intercellular adhesion molecule 1,monocyte chemoattractant protein-1,endothelial nitric oxide synthase,heat shock protein 70,hypoxia inducible factor 1 alpha,lysyl oxidase,intelectin 1,mitogen-activated protein kinase 14,toll-like receptors,osteoprotegerin,vitamin D receptor,and fibrinogen may be associated with the development of DFU.However,considering the limitations of the present investigations,future multi-center studies with larger sample sizes,as well as in-depth mechanistic research are warranted.

Acetabular Development Following Salter’s Innominate Osteotomy for the Treatment of Developmental Dysplasia of the Hip: Long Term Follow-Up

Aim: To investigate the long term results of the patients followed till the skeletal maturity and treated with Salter innominate osteotomy. Patients and Methods: 85 hips of 63 patients whom were operated by the same surgeon between the years 1985 and 1991 were evaluated retrospectively. 34 hips of 25 patients who did not have enough follow-up or did not reach skeletal maturity at their last radiographic control were excluded from the study. So, 51 hips of 38 patients were included into our study. Mean age of the patients at the time of operation was 3 years 2 months (1.5 - 11 years), mean follow-up time was 16 years 6 months (10 - 23 years) and mean age at the last control was 19 years 7 months (15 - 27 years). Results: The overall clinical results were favorable (excellent or good) in 48 hips (94.1%) according to the modified McKay clinical evaluation scale. Avascular necrosis was evaluated with the Kalamchi-McEven classification at the last follow up and 45 hips (88.2%) had no avascular necrosis. The radiographic results were assessed by the Severin classification system and 10 hips (19.6%) were stage 1a;10 hips (19.6%) were stage 1b;and 30 hips (58.8%) were stage 2. Upon the analysis of our radiographic results according to Stulberg classification system, we found out that only 2 (3.9%) of our patients were Stulberg stage 5, whereas 36 cases (70.6%) were Stulberg stage 1 and 2 (spherical congruency). According to Croft’s classification of hips for degenerative changes, 36 (70.6%) patients were stage 0;6 (11.8%) patients were stage 1;5 (9.8%) patients were stage 2 and 4 patients (8.7%) were stage 3. Conclusion: When appropriate soft tissue balance is provided, the complications of Salter Innominate Osteotomy are decreased and thus, it provides an excellent functional and radiological result.

Endothelial PDGF-BB/PDGFR-βsignaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation

The mechanisms that coordinate the shift from joint homeostasis to osteoarthritis(OA)remain unknown.No pharmacological intervention can currently prevent the progression of osteoarthritis.Accumulating evidence has shown that subchondral bone deterioration is a primary trigger for overlying cartilage degeneration.We previously found that H-type vessels modulate aberrant subchondral bone formation during the pathogenesis of OA.However,the mechanism responsible for the elevation of H-type vessels in OA is still unclear.Here,we found that PDGFR-βexpression,predominantly in the CD31^(hi)Emcn^(hi) endothelium,was substantially elevated in subchondral bones from OA patients and rodent OA models.A mouse model of OA with deletion of PDGFR-βin endothelial cells(ECs)exhibited fewer H-type vessels,ameliorated subchondral bone deterioration and alleviated overlying cartilage degeneration.Endothelial PDGFR-βpromotes angiogenesis through the formation of the PDGFR-β/talin1/FAK complex.Notably,endothelium-specific inhibition of PDGFR-βby local injection of AAV9 in subchondral bone effectively attenuated the pathogenesis of OA compared with that of the vehicle-treated controls.Based on the results from this study,targeting PDGFR-βis a novel and promising approach for the prevention or early treatment of OA.

Cross-talk between biometal ions and immune cells for bone repair

Biometal ions are crucial in the structure and function of living organisms and have extensively been employed to promote bone tissue regeneration.Nevertheless,the biological functions of biometal ions and the underlying mechanisms responsible for their pro-regenerative effects remain incompletely understood,since bone repair is an intricate physiological process involving multiple cell types and signals.Recent accomplishments in the osteoim-munological field have revealed the momentous involvement of the immune system in mediating the therapeutic effects of biometal ions.The inflammatory factors secreted by immune cells contribute to bone cell migration,activation,and proliferation.This review summarizes the immune system and its constituent cells,followed by the current perspective on immunomodulation during bone healing.Next,the physicochemical and physiological properties of various biometal ions,including lithium,sodium,potassium,magnesium,calcium,strontium,vana-dium,iron,cobalt,copper,and zinc,are thoroughly reviewed.In addition,the interactions between biometal ions,immune cells,and bone tissue are discussed,aiming to provide insights into the prospective development of novel approaches to bone tissue regeneration by harnessing the therapeutic potential of these biometal ions.

Novel injectable adhesive hydrogel loaded with exosomes for holistic repair of hemophilic articular cartilage defect

Hemophilic articular cartilage damage presents a significant challenge for surgeons,characterized by recurrent intraarticular bleeding,a severe inflammatory microenvironment,and limited self-repair capability of cartilage tissue.Currently,there is a lack of tissue engineering-based integrated therapies that address both early hemostasis,anti-inflammation,and long-lasting chondrogenesis for hemophilic articular cartilage defects.Herein,we developed an adhesive hydrogel using oxidized chondroitin sulfate and gelatin,loaded with exosomes derived from bone marrow stem cells(BMSCs)(Hydrogel-Exos).This hydrogel demonstrated favorable injectability,self-healing,biocompatibility,biodegradability,swelling,frictional and mechanical properties,providing a comprehensive approach to treating hemophilic articular cartilage defects.The adhesive hydrogel,featuring dynamic Schiff base bonds and hydrogen bonds,exhibited excellent wet tissue adhesiveness and hemostatic properties.In a pig model,the hydrogel could be smoothly injected into the knee joint cartilage defect site and gelled in situ under fluid-irrigated arthroscopic conditions.Our in vitro and in vivo experiments confirmed that the sustained release of exosomes yielded anti-inflammatory effects by modulating macrophage M2 polarization through the NF-κB pathway.This immunoregulatory effect,coupled with the extracellular matrix components provided by the adhesive hydrogel,enhanced chondrogenesis,promoted the cartilage repair and joint function restoration after hemophilic articular cartilage defects.In conclusion,our results highlight the significant application potential of Hydrogel-Exos for early hemostasis,immunoregulation,and long-term chondrogenesis in hemophilic patients with cartilage injuries.This innovative approach is well-suited for application during arthroscopic procedures,offering a promising solution for addressing the complex challenges associated with hemophilic articular cartilage damage.

Unique immunological profile in patients with COVID-19

The relationship between severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)and host immunity is poorly understood.We performed an extensive analysis of immune responses in 32 patients with severe COVID-19,some of whom succumbed A control population of healthy subjects was included.Patients with COVID-19 had an altered distribution of peripheral blood lymphocytes,with an increased proportion of mature natural killer(NK)cells and low T-cell numbers.NK cells and CD8^(+)T cells overexpressed T-cellimmunoglobulin and mucin domain-3(TIM-3)and CD69.NK cell exhaustion was attested by increased frequencies of programmed cell death protein 1(PD-1)positive cells and reduced frequencies of natural killer group 2 member D(NKG2D)-,DNAX accessory molecule-1(DNAM-1)-and sialic acid-binding Ig-like lectin 7(Siglec-7)-expressing NK cells,associated with a reduced ability to secrete interferon(IFN)γ.Patients with poor outcome showed a contraction of immature CD56^(bright) and an expansion of mature CD57^(+)F_(CEI)Rlγ^(eng) adaptive NK cells compared to survivors.Increased serum levels of IL-6 were also more frequently identified in deceased patients compared to survivors.Of note,monocytes secreted abundant quantities of IL-6,IL-8,and IL-1β which persisted at lower levels several weeks after recovery with concomitant normalization of CD69,PD-1 and TIM-3 expression and restoration of CD8^(+)T cell numbers.A hyperactivated/exhausted immune response dominate in severe SARS-CoV-2 infection,probably driven by an uncontrolled secretion of inflammatory cytokines by monocytes.These findings unveil a unique immunological profile in COVID-19 patients that will help to design effective stage-specific treatments for this potentially deadly disease.

Triple-functional bone adhesive with enhanced internal fixation,bacteriostasis and osteoinductive properties for open fracture repair

At present,effective fixation and anti-infection implant materials represent the mainstay for the treatment of open fractures.However,external fixation can cause nail tract infections and is ineffective for fixing small fracture fragments.Moreover,closed reduction and internal fixation during the early stage of injury can lead to potential bone infection,conducive to bone nonunion and delayed healing.Herein,we designed a bone adhesive with anti-infection,osteogenic and bone adhesion fixation properties to promote reduction and fixation of open fractures and subsequent soft tissue repair.It was prepared by the reaction of gelatin(Gel)and oxidized starch(OS)with vancomycin(VAN)-loaded mesoporous bioactive glass nanoparticles(MBGNs)covalently cross-linked with Schiff bases.Characterization and adhesion experiments were conducted to validate the successful preparation of the Gel-OS/VAN@MBGNs(GOVM-gel)adhesive.Meanwhile,in vitro cell experiments demonstrated its good antibacterial effects with the ability to stimulate bone marrow mesenchymal stem cell(BMSCs)proliferation,upregulate the expression of alkaline phosphatase(ALP)and osteogenic proteins(RunX2 and OPN)and enhance the deposition of calcium nodules.Additionally,we established a rat skull fracture model and a subcutaneous infection model.The histological analysis showed that bone adhesive enhanced osteogenesis,and in vivo experiments demonstrated that the number of inflammatory cells and bacteria was significantly reduced.Overall,the adhesive could promote early reduction of fractures and antibacterial and osteogenic effects,providing the foothold for treatment of this patient population.

Exosomes-loaded electroconductive nerve dressing for nerve regeneration and pain relief against diabetic peripheral nerve injury

Over the years,electroconductive hydrogels(ECHs)have been extensively applied for stimulating nerve regeneration and restoring locomotor function after peripheral nerve injury(PNI)with diabetes,given their favorable mechanical and electrical properties identical to endogenous nerve tissue.Nevertheless,PNI causes the loss of locomotor function and inflammatory pain,especially in diabetic patients.It has been established that bone marrow stem cells-derived exosomes(BMSCs-Exos)have analgesic,anti-inflammatory and tissue regeneration properties.Herein,we designed an ECH loaded with BMSCs-Exos(ECH-Exos)electroconductive nerve dressing to treat diabetic PNI to achieve functional recovery and pain relief.Given its potent adhesive and self-healing properties,this laminar dressing is convenient for the treatment of damaged nerve fibers by automatically wrapping around them to form a size-matched tube-like structure,avoiding the cumbersome implantation process.Our in vitro studies showed that ECH-Exos could facilitate the attachment and migration of Schwann cells.Meanwhile,Exos in this system could modulate M2 macrophage polarization via the NF-κB pathway,thereby attenuating inflammatory pain in diabetic PNI.Additionally,ECH-Exos enhanced myelinated axonal regeneration via the MEK/ERK pathway in vitro and in vivo,consequently ameliorating muscle denervation atrophy and further promoting functional restoration.Our findings suggest that the ECH-Exos system has huge prospects for nerve regeneration,functional restoration and pain relief in patients with diabetic PNI.