TrkA-mediated sensory innervation of injured mouse tendon supports tendon sheath progenitor cell expansion and tendon repair.

Peripheral neurons terminate at the surface of tendons partly to relay nociceptive pain signals; however, the role of peripheral nerves in tendon injury and repair remains unclear. Here, we show that after Achilles tendon injury in mice, there is new nerve growth near tendon cells that express nerve growth factor (NGF). Conditional deletion of the Ngf gene in either myeloid or mesenchymal mouse cells limited both innervation and tendon repair. Similarly, inhibition of the NGF receptor tropomyosin receptor kinase A (TrkA) abrogated tendon healing in mouse tendon injury. Sural nerve transection blocked the postinjury increase in tendon sensory innervation and the expansion of tendon sheath progenitor cells (TSPCs) expressing tubulin polymerization promoting protein family member 3. Single cell and spatial transcriptomics revealed that disruption of sensory innervation resulted in dysregulated inflammatory signaling and transforming growth factor-ß (TGFß) signaling in injured mouse tendon. Culture of mouse TSPCs with conditioned medium from dorsal root ganglia neuron further supported a role for neuronal mediators and TGFß signaling in TSPC proliferation. Transcriptomic and histologic analyses of injured human tendon biopsy samples supported a role for innervation and TGFß signaling in human tendon regeneration. Last, treating mice after tendon injury systemically with a small-molecule partial agonist of TrkA increased neurovascular response, TGFß signaling, TSPC expansion, and tendon tissue repair. Although further studies should investigate the potential effects of denervation on mechanical loading of tendon, our results suggest that peripheral innervation is critical for the regenerative response after acute tendon injury.

Multi-omic single cell analysis resolves novel stromal cell populations in healthy and diseased human tendon.

Tendinopathy accounts for over 30% of primary care consultations and represents a growing healthcare challenge in an active and increasingly ageing population. Recognising critical cells involved in tendinopathy is essential in developing therapeutics to meet this challenge. Tendon cells are heterogenous and sparsely distributed in a dense collagen matrix; limiting previous methods to investigate cell characteristics ex vivo. We applied next generation CITE-sequencing; combining surface proteomics with in-depth, unbiased gene expression analysis of > 6400 single cells ex vivo from 11 chronically tendinopathic and 8 healthy human tendons. Immunohistochemistry validated the single cell findings. For the first time we show that human tendon harbours at least five distinct COL1A1/2 expressing tenocyte populations in addition to endothelial cells, T-cells, and monocytes. These consist of KRT7/SCX+ cells expressing microfibril associated genes, PTX3+ cells co-expressing high levels of pro-inflammatory markers, APOD+ fibro-adipogenic progenitors, TPPP3/PRG4+ chondrogenic cells, and ITGA7+ smooth muscle-mesenchymal cells. Surface proteomic analysis identified markers by which these sub-classes could be isolated and targeted in future. Chronic tendinopathy was associated with increased expression of pro-inflammatory markers PTX3, CXCL1, CXCL6, CXCL8, and PDPN by microfibril associated tenocytes. Diseased endothelium had increased expression of chemokine and alarmin genes including IL33.

Fracture healing in the elderly: A review.

Older patients are commonly at a higher risk of experiencing a bone fracture. Complications during fracture healing, including delayed union and non-union, can arise as a result of a multitude of patient and treatment factors. This review describes those factors which contribute to a greater risk of delayed union and non-union with particular reference to the elderly population and discusses therapies that may enhance the fracture healing process in the hope of reducing the incidence of delayed union and non-union. Increasing age does seem to increase the risk of delayed union or non-union. In addition, smoking and the treatment of post-fracture pain with non-steroidal anti-inflammatory drugs (NSAIDs) put the patient at the greatest risk, while ultrasound therapy appears to be a non-invasive, effective treatment option to reduce the risk of delayed union or non-union. The use of growth factors and of stem cells and the role of surgery are also discussed.

Induced Foxp3(+) T Cells Colonizing Tolerated Allografts Exhibit the Hypomethylation Pattern Typical of Mature Regulatory T Cells.

Regulatory T cells expressing the transcription factor Foxp3 require acquisition of a specific hypomethylation pattern to ensure optimal functional commitment, limited lineage plasticity, and long-term maintenance of tolerance. A better understanding of the molecular mechanisms involved in the generation of these epigenetic changes in vivo will contribute to the clinical exploitation of Foxp3(+) Treg. Here, we show that both in vitro and in vivo generated antigen-specific Foxp3(+) Treg can acquire Treg-specific epigenetic characteristics and prevent skin graft rejection in an animal model.

Mortality rates at 10 years after metal-on-metal hip resurfacing compared with total hip replacement in England.

STUDY QUESTION: How do 10 year mortality rates compare between patients undergoing metal-on-metal (MoM) hip resurfacing and those undergoing total hip replacement in England? SUMMARY ANSWER: Patients in England with hip osteoarthritis who underwent MoM hip resurfacing between 1999 and 2012 have reduced long term mortality compared with those who underwent cemented and uncemented THR.

Complications of minimally invasive calcaneal osteotomy versus open osteotomy.

BACKGROUND: Calcaneal osteotomy is an established technique for correcting hindfoot deformity. Patients traditionally receive an osteotomy through the open lateral approach to the calcaneus. To reduce the rate of wound complications associated with a direct open lateral approach, a minimally invasive surgical (MIS) technique has been adopted. This uses a low-speed, high-torque burr to perform the same osteotomy under radiographic guidance. We hypothesized that the new MIS calcaneal osteotomy would be a safe alternative to open calcaneal osteotomy while obtaining the same displacement. METHODS: The safety of the new MIS technique was investigated with a case controlled study on all patients who underwent displacement calcaneal osteotomy at the Nuffield Orthopaedic Centre from 2008 to 2014. The primary outcome measure was 30 day postoperative complication rate. Secondary outcome measures included operating time, duration of stay, fusion rates, and calcaneal displacement. Eighty-one patients underwent calcaneal osteotomy as part of their corrective surgery, 50 in the Open approach group and 31 in MIS group. The average age was 47.7 years (range 16-77) for the Open group and 50.1 (range 21-77) in the MIS group. RESULTS: A mean calcaneal displacement of 9.4 mm (SD = 1.16, 8 to 11 mm) and 10.2 mm (SD = 1.06, 8 to 13 mm) was achieved through the MIS and Open approaches, respectively. There were significantly fewer wound complications in the MIS group (6.45%) compared to the Open group (28%, P = .022). The MIS group was associated with significantly lower rate of wound infection (3% versus 20%, P = .044). Three patients in the Open group experienced sural peripheral neuropathy. The average length of stay was 3.8 days following MIS and 4.3 days following open calcaneal osteotomy. Nonunion occurred in only 1 patient in the MIS group and none in the open group. CONCLUSIONS: MIS calcaneal osteotomy was found to be a safe technique. It was technically as effective as calcaneal osteotomy performed through an open lateral approach but was associated with significantly fewer wound complications and fewer nerve complications. LEVEL OF EVIDENCE: Level III, comparative study.

Arthroscopic ankle fusion for avascular necrosis of the talus.

BACKGROUND: Avascular necrosis (AVN) of the talus is a painful condition leading to destruction of the ankle-hindfoot complex. Moderate outcomes and high complication rates are reported in small numbers of advanced disease treated with tibiotalocalcaneal fusion, which has the additional disadvantage of sacrificing both the ankle and subtalar joints. The blood supply of the talus is tenuous, and open procedures risk further talar collapse by disrupting extraosseous vessels. This article reports the outcome of arthroscopic ankle fusion for late-stage AVN of the talus. Our hypothesis was that arthroscopic ankle fusion would relieve symptoms of advanced talar AVN, prevent collapse of the talus, and preserve the subtalar joint. METHODS: A cohort study was performed on 16 patients with talar AVN treated with arthroscopic ankle fusion. Our primary outcome was fusion rate. Secondary outcomes included perioperative complications, ongoing pain, and further operative intervention. All radiologic investigations were reported independently by a senior radiologist. The average age of the patients was 53.5 years. The presumed causes of talar AVN were steroids, trauma, hematologic disorders, and alcoholism. The etiology was unknown in 7 patients. One patient was lost to follow-up. RESULTS: Clinical and radiologic fusion at the ankle joint was confirmed in 15 of 15 available patients. Thirteen patients reported resolution of pain at follow-up. Three patients had ongoing pain and underwent a subsequent successful subtalar fusion. CONCLUSIONS: Arthroscopic ankle fusion was a safe and reliable treatment of symptomatic advanced talar AVN. It was a minimally invasive procedure with minimal complication rate, preserving the talus and sparing the subtalar joint. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Mortality rates at 10 years after metal-on-metal hip resurfacing compared with total hip replacement in England: retrospective cohort analysis of hospital episode statistics.

OBJECTIVES: To compare 10 year mortality rates among patients undergoing metal-on-metal hip resurfacing and total hip replacement in England. DESIGN: Retrospective cohort study. SETTING: English hospital episode statistics database linked to mortality records from the Office for National Statistics. POPULATION: All adults who underwent primary elective hip replacement for osteoarthritis from April 1999 to March 2012. The exposure of interest was prosthesis type: cemented total hip replacement, uncemented total hip replacement, and metal-on-metal hip resurfacing. Confounding variables included age, sex, Charlson comorbidity index, rurality, area deprivation, surgical volume, and year of operation. MAIN OUTCOME MEASURES: All cause mortality. Propensity score matching was used to minimise confounding by indication. Kaplan-Meier plots estimated the probability of survival up to 10 years after surgery. Multilevel Cox regression modelling, stratified on matched sets, described the association between prosthesis type and time to death, accounting for variation across hospital trusts. RESULTS: 7437 patients undergoing metal-on-metal hip resurfacing were matched to 22,311 undergoing cemented total hip replacement; 8101 patients undergoing metal-on-metal hip resurfacing were matched to 24,303 undergoing uncemented total hip replacement. 10 year rates of cumulative mortality were 271 (3.6%) for metal-on-metal hip resurfacing versus 1363 (6.1%) for cemented total hip replacement, and 239 (3.0%) for metal-on-metal hip resurfacing versus 999 (4.1%) for uncemented total hip replacement. Patients undergoing metal-on-metal hip resurfacing had an increased survival probability (hazard ratio 0.51 (95% confidence interval 0.45 to 0.59) for cemented hip replacement; 0.55 (0.47 to 0.65) for uncemented hip replacement). There was no evidence for an interaction with age or sex. CONCLUSIONS: Patients with hip osteoarthritis undergoing metal-on-metal hip resurfacing have reduced mortality in the long term compared with those undergoing cemented or uncemented total hip replacement. This difference persisted after extensive adjustment for confounding factors available in our data. The study results can be applied to matched populations, which exclude patients who are very old and have had complex total hip replacements. Although residual confounding is possible, the observed effect size is large. These findings require validation in external cohorts and randomised clinical trials.

Foxp3 expression is required for the induction of therapeutic tissue tolerance.

CD4(+)Foxp3(+) regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGF-ß-dependent manner. Foxp3(+) Treg are also required to achieve tolerance to transplanted tissues when induced by coreceptor or costimulation blockade. Using TCR-transgenic mice to avoid issues of autoimmune pathology, we show that Foxp3 expression is both necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGF-ß signaling to T cells can wholly be explained by its role in induction of Foxp3, as such signaling proved dispensable for the suppressive process. We analyzed the relative contribution of TGF-ß and Foxp3 to the transcriptome of TGF-ß-induced Treg and showed that TGF-ß elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral-mediated conditional nuclear expression of Foxp3 proved sufficient to confer transplant-suppressive potency on CD4(+) T cells and was lost once nuclear Foxp3 expression was extinguished. These data support a dual role for TGF-ß and Foxp3 in induced tolerance, in which TGF-ß stimulates Foxp3 expression, for which sustained expression is then associated with acquisition of tolerance.

Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance.

A paradigm shift in immunology has been the recent discovery of regulatory T cells (T reg cells), of which CD4(+)Foxp3(+) cells are proven as essential to self-tolerance. Using transgenic B6.Foxp3(hCD2) mice to isolate and ablate Foxp3(+) T reg cells with an anti-hCD2 antibody, we show for the first time that CD4(+)Foxp3(+) cells are crucial for infectious tolerance induced by nonablative anti-T cell antibodies. In tolerant animals, Foxp3(+) T reg cells are constantly required to suppress effector T cells still capable of causing tissue damage. Tolerated tissue contains T cells that are capable of rejecting it, but are prevented from doing so by therapeutically induced Foxp3(+) T reg cells. Finally, Foxp3(+) cells have been confirmed as the critical missing link through which infectious tolerance operates in vivo. Peripherally induced Foxp3(+) cells sustain tolerance by converting naive T cells into the next generation of Foxp3(+) cells. Empowering Foxp3(+) regulatory T cells in vivo offers a tractable route to avoid and correct tissue immunopathology.

Infectious tolerance: therapeutic potential.

Infectious tolerance describes an in vivo process in which tolerance is passed on from one population of lymphocytes to another. In this way, short-term therapy aimed at generating infectious tolerance has the potential to achieve long term, self-perpetuating immune homeostasis in a clinical setting. In recent years, a number of differing strategies have successfully achieved tolerance in vivo. These include harnessing regulatory T cells and tolerogenic antigen presenting cells, promoting tolerogenic interactions or inhibiting activation of effector cells. Many of these are just beginning to face the harsh realities of the therapeutics industry.