Fibroblast growth factor (FGF) signaling in development and skeletal diseases

AbstractFibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development

Epigenetic Regulation of Mesenchymal Stem Cells: A Focus on Osteogenic and Adipogenic Differentiation

Stem cells are characterized by their capability to self-renew and terminally differentiate into multiple cell types. Somatic or adult stem cells have a finite self-renewal capacity and are lineage-restricted. The use of adult stem cells for therapeutic purposes has been a topic of recent interest given the ethical considerations associated with embryonic stem (ES) cells. Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into osteogenic, adipogenic, chondrogenic, or myogenic lineages. Owing to their ease of isolation and unique characteristics, MSCs have been widely regarded as potential candidates for tissue engineering and repair. While various signaling molecules important to MSC differentiation have been identified, our complete understanding of this process is lacking. Recent investigations focused on the role of epigenetic regulation in lineage-specific differentiation of MSCs have shown that unique patterns of DNA methylation and histone modifications play an important role in the induction of MSC differentiation toward specific lineages. Nevertheless, MSC epigenetic profiles reflect a more restricted differentiation potential as compared to ES cells. Here we review the effect of epigenetic modifications on MSC multipotency and differentiation, with a focus on osteogenic and adipogenic differentiation. We also highlight clinical applications of MSC epigenetics and nuclear reprogramming

Defective Osteogenic Differentiation in the Development of Osteosarcoma

Osteosarcoma (OS) is associated with poor prognosis due to its high incidence of metastasis and chemoresistance. It often arises in areas of rapid bone growth in long bones during the adolescent growth spurt. Although certain genetic conditions and alterations increase the risk of developing OS, the molecular pathogenesis is poorly understood. Recently, defects in differentiation have been linked to cancers, as they are associated with high cell proliferation. Treatments overcoming these defects enable terminal differentiation and subsequent tumor inhibition. OS development may be associated with defects in osteogenic differentiation. While early regulators of osteogenesis are unable to bypass these defects, late osteogenic regulators, including Runx2 and Osterix, are able to overcome some of the defects and inhibit tumor propagation through promoting osteogenic differentiation. Further understanding of the relationship between defects in osteogenic differentiation and tumor development holds tremendous potential in treating OS

Bone Morphogenetic Proteins in Craniofacial Surgery: Current Techniques, Clinical Experiences, and the Future of Personalized Stem Cell Therapy

Critical-size osseous defects cannot heal without surgical intervention and can pose a significant challenge to craniofacial reconstruction. Autologous bone grafting is the gold standard for repair but is limited by a donor site morbidity and a potentially inadequate supply of autologous bone. Alternatives to autologous bone grafting include the use of alloplastic and allogenic materials, mesenchymal stem cells, and bone morphogenetic proteins. Bone morphogenetic proteins (BMPs) are essential mediators of bone formation involved in the regulation of differentiation of osteoprogenitor cells into osteoblasts. Here we focus on the use of BMPs in experimental models of craniofacial surgery and clinical applications of BMPs in the reconstruction of the cranial vault, palate, and mandible and suggest a model for the use of BMPs in personalized stem cell therapies

Review Article Bone Morphogenetic Proteins in Craniofacial Surgery: Current Techniques, Clinical Experiences, and the Future of Personalized Stem Cell Therapy

Critical-size osseous defects cannot heal without surgical intervention and can pose a significant challenge to craniofacial reconstruction. Autologous bone grafting is the gold standard for repair but is limited by a donor site morbidity and a potentially inadequate supply of autologous bone. Alternatives to autologous bone grafting include the use of alloplastic and allogenic materials, mesenchymal stem cells, and bone morphogenetic proteins. Bone morphogenetic proteins (BMPs) are essential mediators of bone formation involved in the regulation of differentiation of osteoprogenitor cells into osteoblasts. Here we focus on the use of BMPs in experimental models of craniofacial surgery and clinical applications of BMPs in the reconstruction of the cranial vault, palate, and mandible and suggest a model for the use of BMPs in personalized stem cell therapies

Bone morphogenetic protein-9 effectively induces osteogenic differentiation of reversibly immortalized calvarial mesenchymal progenitor cells

AbstractCritical-sized craniofacial defect repair represents a significant challenge to reconstructive surgeons. Many strategies have been employed in an effort to achieve both a functionally and cosmetically acceptable outcome. Bone morphogenetic proteins (BMPs) provide a robust osteoinductive cue to stimulate bony growth and remodeling. Previous studies have suggested that the BMP-9 isoform is particularly effective in promoting osteogenic differentiation of mesenchymal progenitor cells. The aim of this study is to characterize the osteogenic capacity of BMP-9 on calvarial mesenchymal progenitor cell differentiation. Reversibly immortalized murine calvarial progenitor cells (iCALs) were infected with adenoviral vectors encoding BMP-9 or GFP and assessed for early and late stages of osteogenic differentiation in vitro and for osteogenic differentiation via in vivo stem cell implantation studies. Significant elevations in alkaline phosphatase (ALP) activity, osteocalcin (OCN) mRNA transcription, osteopontin (OPN) protein expression, and matrix mineralization were detected in BMP-treated cells compared to control. Specifically, ALP activity was elevated on days 3, 7, 9, 11, and 13 post-infection and OCN mRNA expression was elevated on days 8, 10, and 14 in treated cells. Additionally, treatment groups demonstrated increased OPN protein expression on day 10 and matrix mineralization on day 14 post-infection relative to control groups. BMP-9 also facilitated the formation of new bone in vivo as detailed by gross, microcomputed tomography, and histological analyses. Therefore, we concluded that BMP-9 significantly stimulates osteogenic differentiation in iCALs, and should be considered an effective agent for calvarial tissue regeneration

SSET Project: Cost-effectiveness Analysis of Surgical Specialty Emergency Trays in the Emergency Department

Background:. We hypothesize that reusable, on-site specialty instrument trays available to plastic surgery residents in the emergency department (ED) for bedside procedures are more cost-effective than disposable on-site and remote re-usable operating room (OR) instruments at our institution. Methods:. We completed a cost-effectiveness analysis comparing the use of disposable on-site kits and remote OR trays to a hypothetical, custom, reusable tray for ED procedures completed by PRS residents. Material costs of existing OR trays were used to estimate the purchasing and use-cost of a custom on-site tray for the same procedures. Cost of per procedure ‘consult time’ was estimated using procedure and resident salary. Results:. Sixteen bedside procedures were completed over a 4.5 month period. A mean of 2.14 disposable kits were used per-procedure. Mean consultation time was 1.66 hours. Procedures that used OR trays took 3 times as long as procedures that used on-site kits (4 vs. 1.1 hours). Necessary, additional instruments were unavailable for 75% of procedures. Mean cost of using disposable kits and OR trays was $115.03/procedure versus an estimated$26.67/procedure cost of using a custom tray, yielding $88.36/procedure cost-savings. Purchase of a single custom tray ($1,421.55) would be redeemed after 2.3 weeks at 1 procedure/day. Purchasing 4 trays has projected annual cost-savings of $26,565.20. Conclusion:. The purchase of specialized procedure trays will yield valuable time and cost-savings while providing quality patient care. Improving time efficiency will help achieve the Accreditation Council of Graduate Medical Education (ACGME) goals of maintaining resident well-being and developing quality improvement competency

A Scoping Review of Mobile Apps in Plastic Surgery: Patient Care, Trainee Education, and Professional Development

Background:. Over the past 10 years, smartphones have become ubiquitous, and mobile apps serve a seemingly endless number of functions in our everyday lives. These functions have entered the realm of plastic surgery, impacting patient care, education, and delivery of services. This article reviews the current uses of plastic surgery mobile apps, app awareness within the plastic surgery community, and the ethical issues surrounding their use in patient care. Methods:. A scoping review of electronically available literature within PubMed, Embase, and Scopus databases was conducted in two waves in November and May 2022. Publications discussing mobile application use in plastic surgery were screened for inclusion. Results:. Of the 80 nonduplicate publications retrieved, 20 satisfied the inclusion criteria. Articles acquired from the references of these publications were reviewed and summarized when relevant. The average American Society of Plastic Surgeons evidence rating of the publications was 4.2. Applications could be categorized broadly into three categories: patient care and surgical applications, professional development and education, and marketing and practice development. Conclusions:. Mobile apps related to plastic surgery have become an abundant resource for patients, attending surgeons, and trainees. Many help bridge gaps in patient care and surgeon-patient communication, and facilitate marketing and practice development. Others make educational content more accessible to trainees and performance assessment more efficient and equitable. The extent of their impact on patient decision-making and expectations has not been completely elucidated