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.

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FGF/FGFR signaling in health and disease

The rate of fracture nonunion averages between 5%[1][1] and 10% for long bones[2][2], and the rate may be increasing with time[3][3]. Nonunion risk is clearly related to the severity of the injury resulting in fracture[4][4]-[10][5]. Randomized clinical trials (RCTs) have also shown that variations

Biological Risk Factors for Nonunion of Bone Fracture.

Background The successful treatment of atrophic tibia non-unions and tibia non-unions with large bone defects or infections is a major challenge in orthopedic and trauma surgery. This article evaluates the use of the ‘diamond concept’ using a one-step or two-step procedure according to ‘Masquelet technique’ in the treatment of atrophic tibia non-unions. Methods Between February 2010 and March 2014, 102 patients with atrophic non-unions were treated according to the ‘diamond concept’ in our center. Ninety-nine were available for follow-up. Forty-nine received a one-step treatment (Group 1, G1) and 50 patients received a two-step treatment according to the ‘Masquelet technique’ (Group 2, G2). Clinical and radiological parameters were measured preoperatively as well as 4, 6, and 12 weeks and 6 and 12 months postoperatively. In order to evaluate the subjective health of patients, we used the SF-12 questionnaire. Data analysis was performed one year after treatment. Results The rate of consolidation in G1 was 84% and 80% in G2. The time to heal in G2 was 8.6 ± 2.9 months, which is significantly longer than in G1 being 6.9 ± 3.1 months. In comparison patients in G1/G2 had an average of 3.2/6.7 previous major surgeries. In G1, 4 of 8 patients who did not heal successfully showed positive intraoperative cultures. In G2, 26 patients (52%) initially presented with positive cultures. The results of the SF-12 questionnaire improved in both groups during the postoperative follow-up, but showed no significant differences between groups. In 29 patients a gentamycin-coated nail was used for reosteosynthesis. These patients showed by trend a lower rate of complications at a higher rate of consolidation. Conclusions Our study showed that the ‘diamond concept’ is a suitable method for safely and effectively treating non-unions with large defects or infections. The use of an antibiotic-coated nail provides a therapeutic benefit. For large bone defects of infected non-unions the two-step procedure after Masquelet is an efficient way to eradicate the infection and treat the bone defect successfully.

Treatment of atrophic tibia non-unions according to 'diamond concept': Results of one- and two-step treatment

The aim of this retrospective study with prospectively documented data was to report the clinical results of treatment of long bone non-unions using the “diamond concept”. Over a 4-year period, patients that presented with a long bone non-union and were managed with the diamond conceptual framework of bone repair were evaluated. Exclusion criteria were hypertrophic, pathological, and infected non-unions. Fixation was revised as it was indicated whilst biological enhancement included the implantation of RIA graft, BMP-7 and concentrated bone marrow aspirate. Data recorded included patient demographics, initial fracture pattern and type of stabilisation, number of previous interventions, time to reoperation, time to union and functional outcome. Painless full weight bearing defined clinical union. Radiological union was defined as the presence of mature callous bridging to at least 3 bone cortices. The minimum follow up was 12 months (range 12–32). In total 64 patients (34 males) with a mean age of 45 years (17–83) were evaluated. Anatomical distribution of non-unions included the femur (54.68%), tibia (34.38%), humerus (4.68%), radius (3.13%) and clavicle (3.13%). The median number of previous interventions was 1 (range 1–5). The majority of patients (82.62%) underwent revision of fixation whereas only bone grafting was performed 9.38% of patients. Three patients developed superficial wound infection (one was MRSA), 1 had deep vein thrombosis and 1 developed heterotopic bone formation. Union was successful in 63/64 (98.4%) non-unions at a mean time of 6 months (range 3–12). All patients were mobilising pain free and returned to their daily living activities at the final follow up. The application of the “diamond concept” in this cohort of patients was associated with a high union rate by providing an optimal mechanical and biological environment. Such an approach should be considered in the surgeon's armamentarium particularly in such cases where difficulty of bone repair is foreseen.

Long bone non-unions treated with the diamond concept: a case series of 64 patients.

Osteoimmunology research is a new emerging research field that investigates the links between the bone and immune responses. Results from osteoimmunology studies suggest that bone is not only an essential component of the musculoskeletal system, but is also actively involved in immune regulation. Many important factors involved in immune regulation also participate in bone homeostasis. Bone homeostasis is achieved by a coordinated action between bone-synthesizing osteoblasts and bone-degrading osteoclasts. An imbalanced action between osteoblasts and osteoclasts often results in pathological bone diseases: osteoporosis is caused by an excessive osteoclast activity, whereas osteopetrosis results from an increased osteoblast activity. This review focuses on dendritic cell-specific transmembrane protein (DC-STAMP), an important protein currently considered as a master regulator of osteoclastogenesis. Of clinical relevance, the frequency of circulating DC-STAMP+ cells is elevated during the pathogenesis of psoriatic diseases. Intriguingly, recent results suggest that DC-STAMP also plays an imperative role in bone homeostasis by regulating the differentiation of both osteoclasts and osteoblasts. This article summarizes our current knowledge on DC-STAMP by focusing on its interacting proteins, its regulation on osteoclastogenesis-related genes, its possible involvement in immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated signaling cascade, and its potential of developing therapeutics for clinical applications. J. Cell. Physiol. 231: 2402-2407, 2016. © 2016 Wiley Periodicals, Inc.

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DC‐STAMP: A Key Regulator in Osteoclast Differentiation

The aim of this study was to assess the union rates in a series of patients with failed femoral shaft aseptic non-union who were treated with percutaneous concentrated autologous bone marrow grafting. Bone marrow harvesting and cell injection were performed under general anaesthesia in a single surgical procedure. Radiographic union was diagnosed in fractures with a score ≥ 10 according to the radiographic union scale in tibial fractures (RUST) and confirmed by clinical examination. Eight out of 16 patients progressed to consolidation (RUST score ≥ 10). Radiographic evidence of fracture union was observed at an average of 4.75 ± 1.75 months (range 3 to 8 months). All eight patients who did not progress to union within 12 months following the cell grafting procedure had a RUST score ≤ 10 (range 4 to 9). There were no differences in age, number of previous surgeries, duration of nonunion and preoperative RUST score between the patients that developed solid union and those with failed consolidation. However, a relationship between the number of osteoprogenitors injected and the rate of union was noted, 20.2 ± 8.6 × 10(8) versus 9.8 ± 4.3 × 10(8), p<0.005, between the patients with and without union, respectively. The efficacy of percutaneous autologous concentrated bone marrow grafting seems to be related to the number of osteoprogenitors available in the aspirates. Optimisation of the aspiration technique and concentration process is of paramount importance to increase the incidence of a successful outcome.

The effect of autologous concentrated bone-marrow grafting on the healing of femoral shaft non-unions after locked intramedullary nailing

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jor.22455

Polymorphisms in BMP4 and FGFR1 genes are associated with fracture non-union.

Bone marrow stromal cells (BMSCs) are a valuable resource for skeletal regenerative medicine because of their osteogenic potential. In spite of the very general term “stem cell,” this population of cells is far from homogeneous, and different BMSCs clones have greatly different phenotypic properties and, therefore, potentially different therapeutic potential. Adherence to a culture flask surface is a primary defining characteristic of BMSCs. We hypothesized that based on the adherence time we could obtain an enriched population of cells with a greater therapeutic potential. We characterized two populations of bone marrow-derived cells, those that adhered by three days (R-cells) and those that did not adhere by three days but did by six days (L-cells). Clones derived from L-cells could be induced into adipogenic, chondrogenic, and osteogenic differentiation in vitro. L-cells appeared to have greater proliferative capacity, as manifested by larger colony diameter and clones with higher CD146 expression. Only clones from L-cells developed bone marrow stroma in vivo. We conclude that the use of late adherence of BMSCs is one parameter that can be used to enrich for cells that will constitute a superior final product for cell therapy in orthopedics.

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Verônica Fernandes Vianna

Papers

The effect of autologous concentrated bone-marrow grafting on the healing of femoral shaft non-unions after locked intramedullary nailing

Polymorphisms in BMP4 and FGFR1 genes are associated with fracture non-union.

Late Adherent Human Bone Marrow Stromal Cells Form Bone and Restore the Hematopoietic Microenvironment In Vivo