Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression.

Fibroblast activation protein (Fap) is a serine protease that degrades denatured type I collagen, α2-antiplasmin and FGF21. Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin (Oln). Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis (RA). However, whether Fap plays a critical role in osteoarthritis (OA) remains poorly understood. Here, we found that Fap is significantly elevated in osteoarthritic synovium, while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice. Mechanistically, we found that Fap degrades denatured type II collagen (Col II) and Mmp13-cleaved native Col II. Intra-articular injection of rFap significantly accelerated Col II degradation and OA progression. In contrast, Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA. Genetic deletion of Oln significantly exacerbated OA progression, which was partially rescued by Fap deletion or inhibition. Intra-articular injection of rOln significantly ameliorated OA progression. Taken together, these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

Three-Dimensional Tendon Scaffold Loaded with TGF-ß1 Gene Silencing Plasmid Prevents Tendon Adhesion and Promotes Tendon Repair.

Tendon adhesion formation is associated with the aberrant expression of many genes, and interfering with the expression of these genes can prevent adhesion and promote tendon repair. Recent studies have found that silencing the transforming growth factor ß-1 (TGF-ß1) gene can reduce the occurrence of tendon adhesions. The development of tissue engineering and three-dimensional (3D) printing technology have provided new solutions for tendon repair. In this study, TGF-ß1 gene silencing microRNA (miRNA) based RNAi plasmid was loaded on a 3D tendon scaffold using 3D printing technology. In vitro experiments confirmed the sustained release of plasmid and the good biocompatibility of the printed tendon scaffold. Subsequently, the TGF-ß1 gene silencing plasmid loaded tendon scaffold was implanted in a chicken tendon defect model to evaluate the effect of the scaffold in vivo. The results from biomechanical tests and histological examinations showed that the scaffold not only promoted tendon regeneration but also prevented tendon adhesion, which was conducive to the recovery of biofunction. Evaluation of protein expression showed that the loaded plasmids prevented tendon adhesion and promoted tendon functional repair via silencing of the TGF-ß1 gene.

Lateral to medial fibro-adipogenic degeneration are greater in infraspinatus than supraspinatus following nerve and tendon injury of murine rotator cuff.

Small animal models of massive tears of the rotator cuff (RC) were introduced a decade ago and have been extensively used to study the pathophysiology of chronically injured RC. Transection of rodent suprascapular nerve and RC tendon results in progressive muscle atrophy, fibrosis and fat accumulation and affect the infraspinatus and supraspinatus muscles similarly to that seen in the setting of massive RC tears in humans. The purpose of this study was to perform a comprehensive and detailed analysis of the kinetics of fibrotic scar and adipose tissue development comparing phenotypic differences between chronically injured infraspinatus and supraspinatus. Automatic mosaic imaging was used to create large image of whole infraspinatus or supraspinatus sectioned area for quantification of spatial heterogeneity of muscle damage. Pathologic changes advanced from the lateral site of transection to the medial region far from the transection site. A prominent, accelerated muscle fibrosis and fat accumulation was measured in injured infraspinatus compared to supraspinatus. Furthermore, adipose tissue occupied significantly larger area than that of fibrotic tissue in both muscles but was greater in infraspinatus within 6 weeks post induction of injury. Our findings confirm that infraspinatus is more susceptible to accelerated chronic degeneration and can be used to identify the physiological functions that distinguish between the response of infraspinatus and supraspinatus in the setting of massive tears. Whether these pathologic differences observed in mice are reflected in humans is one key aspect that awaits clarification.

FGF6 enhances muscle regeneration after nerve injury by relying on ERK1/2 mechanism.

BACKGROUND: Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS: In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS: FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION: These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.

Non-fibro-adipogenic pericytes from human embryonic stem cells attenuate degeneration of the chronically injured mouse muscle.

Massive tears of the rotator cuff (RC) are associated with chronic muscle degeneration due to fibrosis, fatty infiltration, and muscle atrophy. The microenvironment of diseased muscle often impairs efficient engraftment and regenerative activity of transplanted myogenic precursors. Accumulating myofibroblasts and fat cells disrupt the muscle stem cell niche and myogenic cell signaling and deposit excess disorganized connective tissue. Therefore, restoration of the damaged stromal niche with non-fibro-adipogenic cells is a prerequisite to successful repair of an injured RC. We generated from human embryonic stem cells (hES) a potentially novel subset of PDGFR-ß+CD146+CD34-CD56- pericytes that lack expression of the fibro-adipogenic cell marker PDGFR-α. Accordingly, the PDGFR-ß+PDGFR-α- phenotype typified non-fibro-adipogenic, non-myogenic, pericyte-like derivatives that maintained non-fibro-adipogenic properties when transplanted into chronically injured murine RCs. Although administered hES pericytes inhibited developing fibrosis at early and late stages of progressive muscle degeneration, transplanted PDGFR-ß+PDGFR-α+ human muscle-derived fibro-adipogenic progenitors contributed to adipogenesis and greater fibrosis. Additionally, transplanted hES pericytes substantially attenuated muscle atrophy at all tested injection time points after injury. Coinciding with this observation, conditioned medium from cultured hES pericytes rescued atrophic myotubes in vitro. These findings imply that non-fibro-adipogenic hES pericytes recapitulate the myogenic stromal niche and may be used to improve cell-based treatments for chronic muscle disorders.

Effect of different fusion types on kinematics of midfoot lateral column: a comparative biomechanical study.

BACKGROUND: This study aimed to compare the biomechanical outcomes of the isolated 4th or 5th tarsometatarsal (TMT) joint arthrodesis with the whole lateral TMT joints arthrodesis. METHODS: Ten cadaveric lower legs underwent isolated 4th TMT joint arthrodesis, 5th TMT joint arthrodesis, and whole lateral TMT joints arthrodesis in sequence. Texson F-scan and K-scanTM joint sensor were used to test the medial and lateral plantar pressure and the pressure of calcaneocuboid joint. RESULTS: Compared with the intact foot, the lateral forefoot pressure increased significantly (P<0.05) after 4th TMT joint fusion. The medial forefoot pressure was significantly lower in the 5th TMT joint fusion than that in the intact foot (P<0.05) and the 4th TMT joint fusion (P<0.05), but higher than that in the whole lateral TMT joints fusion (P<0.05). On the contrary, the lateral forefoot pressure was significantly higher in the 5th TMT joint fusion than that in the intact foot and the 4th TMT joint fusion, but lower than that in the whole lateral TMT joints fusion (P<0.05). The medial forefoot pressure was the lowest (P<0.05) and lateral forefoot pressure was the highest (P<0.05) in the whole lateral TMT joints fusion. The calcaneocuboid joint pressure increased respectively with the intact foot being the lowest, followed by the isolated 4th TMT joint arthrodesis, the isolated 5th TMT joint arthrodesis, and the whole lateral TMT joints arthrodesis (P<0.05). CONCLUSIONS: The isolated 4th or 5th TMT joint arthrodesis has less impact on the pressure of forefoot and adjacent joints than the whole lateral TMT joints arthrodesis. The isolated 4th TMT joint arthrodesis has the lowest influence on the pressure of forefoot and adjacent joints.

Comparative study of surgical and conservative treatments for fifth metatarsal base avulsion fractures (type I) in young adults or athletes.

PURPOSE: This study aimed to investigate the therapeutic effects and complications of minimally invasive surgery in treating displaced avulsion fractures (2-3 mm) of fifth metatarsal base zone I in young adults or athletes. METHODS: Forty-six patients with displaced fifth metatarsal base avulsion fractures were assigned to operative and nonoperative groups by randomization. Patients in nonoperative group were immobilized with plaster, while patients in operative group were treated with closed reduction and fixation with a percutaneous screw. RESULTS: All patients were followed up for 14 months on average (ranging from 12 to 24 months). All cases got primary union except for three patients in nonoperative group with malunion and two with frequent mild to moderate plantar pain. The American Orthopaedic Foot and Ankle Society score was significantly better in operative group at 6 months after treatment ( p < 0.05) but not significantly different at 12 months after treatment ( p > 0.05). The average time of full weight bearing and returning to work was significantly shorter in operative group than nonoperative group ( p < 0.05). CONCLUSION: In young adults or athletes with displaced avulsion fractures of fifth metatarsal base zone I, closed reduction and percutaneous screw fixation provides anatomical stable fixation and early mobilization.

Advances in the treatment of rotator cuff lesions by cytokines.

Rotator cuff tears are one of the most common shoulder problems that usually require operative treatments. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. Although surgical treatments have improved dramatically up to now, shoulder pathology is still challenging to orthopedic surgery primarily because these injuries often respond poorly to treatment and require prolonged rehabilitation. Recent attention has focused on several biologic pathways which can augment function to tendon healing, consequently leading to the identification of growth factors involved in this process. In this review, we discuss the studies published in these few years about these growth factors and their role in rotator cuff healing.

Relationship between changes in muscle fibers and CMAP in skeletal muscle with different stages of aging.

AIM: This study aimed to investigate the relationship between the changes of muscle fibers and the changesof peripheral nerve functions (CMAP) with aging. METHODS: Lewis rats enrolled in this study. Muscle biopsy and CMAP of tibialis anterior (TA) were measured. RESULTS: CMAP amplitudes increased significantly in 6 months (P<0.05). CMAP latencies of peroneal nerves found to be significantly higher in older rats (P<0.05). In 6 months these two muscle fibers went through a significant decrease (P<0.05). Type IIb and type IIx muscle fibers increased significantly in 6 months when compared with those in 1 month (P<0.05). After 6 months, the percentages of type I and type IIa muscle fibers increased as the month increased (P<0.05). The percentages of type IIb muscle fibers and type IIx muscle fibers dropped significantly as the month increased (P<0.05). Type I and type IIa muscle fibers were negatively related to CMAP amplitudes (P<0.05). Type IIb muscle fibers were positively related to CMAP amplitudes (P<0.05). CONCLUSION AND DISCUSSION: There is a shift from the fast types (Type IIx and IIb) to slow types (Type I and IIa) in muscle fibers with agingwhich is consistent with changes in CMAP amplitude of peripheral nerves.

[ADVANCE AND PROSPECT OF Lapidus OPERATION].

UNLABELLED: OBJECTIVE To review the advance of the first tarsometatarsal joint fusion (Lapidus operation) in treating hallux valgus. METHODS: The relevant literature about Lapidus operations in recent years was reviewed and analyzed. RESULTS: Lapidus operation is used to correct deformities through three steps of osteotomy, fusion, and fixation. With the development of this operation and its diversities, surgeons can make adjustment according to the individual differences of state of illness in patients. CONCLUSION: Lapidus operation is the final choice for the hallux valgus, with the operation technology becoming more and more mature and the fixation materials and operative instruments more and more advanced. Lapidus operation will be diversified with the constantly appearance of new technologies like arthroscopy.

Isolated avulsion fractures of lesser tuberosity humerus: a case report and review of the literature.

In this case, a 31 year-old female was diagnosed of isolated fractures of lesser tuberosity humerus. The patient could take early functional training of shoulder joint two days after operation. Although isolated fractures of lesser tuberosity humerus are rare, when pain of anterior shoulder joint after trauma, doctors should consider isolated fractures of lesser tuberosity humerus. As for the therapy methods, they should be chosen according to time length after injury. Most of the patients had no obvious residual functional disability after treatments.