Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi.

BACKGROUND: On activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors, and other inflammatory molecules via the constitutive pathway that remains ill defined. OBJECTIVE: We investigated the role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α and IL-6 in mast cells and macrophages. METHODS: Murine knockout (KO) mouse models (IRAP-KO and kit-Wsh/sh) were used to study inflammatory disease models and to measure and mechanistically investigate cytokine secretion and degranulation in bone marrow-derived mast cells in vitro. RESULTS: IRAP-KO mice are protected from TNF-α-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-α and IL-6 but not IL-10 fail to be efficiently secreted. Moreover, chemical targeting of IRAP endosomes reduced proinflammatory cytokine secretion. Mechanistically, impaired TNF-α export from the Golgi and reduced colocalization of vesicle-associated membrane protein (VAMP) 3-positive TNF-α transport vesicles with syntaxin 4 (aka Stx4) was observed in IRAP-KO mast cells, while VAMP8-dependent exocytosis of secretory granules was facilitated. CONCLUSION: IRAP plays a novel role in mast cell-mediated inflammation through the regulation of exocytic trafficking of cytokines.

Transmission of Chikungunya Virus in an Urban Slum, Brazil.

After a chikungunya outbreak in Salvador, Brazil, we performed a cross-sectional, community-based study of 1,776 inhabitants to determine chikungunya virus (CHIKV) seroprevalence, identify factors associated with exposure, and estimate the symptomatic infection rate. From November 2016 through February 2017, we collected sociodemographic and clinical data by interview and tested serum samples for CHIKV IgG. CHIKV seroprevalence was 11.8% (95% CI 9.8%-13.7%), and 15.3% of seropositive persons reported an episode of fever and arthralgia. Infections were independently and positively associated with residences served by unpaved streets, a presumptive clinical diagnosis of chikungunya, and recall of an episode of fever with arthralgia in 2015-2016. Our findings indicate that the chikungunya outbreak in Salvador may not have conferred sufficient herd immunity to preclude epidemics in the near future. The unusually low frequency of symptomatic disease points to a need for further longitudinal studies to better investigate these findings.

A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease.

The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.

Trends in the Incidence and Mortality of Stroke in Matão, Brazil: The Matão Preventing Stroke (MAPS) Study.

BACKGROUND: Stroke population-based studies in the same setting comparing time trends of rates are a gold standard method to determine the primary prevention status of stroke. Twelve years ago, we measured the stroke incidence and mortality in Matão city, Southeast of Brazil. OBJECTIVE: This second Matão stroke registry study aimed to determine the time trends in the incidence, mortality, case fatality, and functional status of patients with stroke. METHODS: This was a prospective, population-based study known as the Matão Preventing Stroke (MAPS). We determined all incident stroke events that occurred between August 1, 2015, and July 31, 2016. Between the periods of November 1, 2003, to October 31, 2004, and August 1, 2015, to July 31, 2016, the rates were age adjusted to the Brazilian and world population. Functional status was measured by Barthel scale 1 year after the index event. RESULTS: We registered 81 cases of incident stroke. Demographic and cardiovascular risk factors were similar in both periods. The mean age increased by 9%, from 65.2 (95% CI 62.6-67.8) to 71.0 (95% CI 68.1-73.8) years. Between 2003-2004 and 2015-2016, the age-adjusted incidence decreased by 39% (incidence rate ratio [IRR] 0.61; 95% CI 0.46-0.79) and mortality by 50% (IRR 0.50; 95% CI 0.31-0.94). The 1-year case fatality was 26%; approximately 56% of the patients were functionally independent, while 7% had a recurrent stroke. Compared with the results of our first registry study, these outcomes did not differ significantly. CONCLUSION: Our findings agree with those of previous studies, showing a decline in the incidence and mortality of stroke in Brazil. Improvements in local public health care might explain these declines.

Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil.

BACKGROUND: Dengue is an arthropod-borne viral disease with a majority of asymptomatic individuals and clinical manifestations varying from mild fever to severe and potentially lethal forms. An increasing number of genetic studies have outlined the association between host genetic variations and dengue severity. Genes associated to viral recognition and entry, as well as those encoding mediators of the immune response against infection are strong candidates for association studies. OBJECTIVES: The aim of this study was to investigate the association between MBL2, CLEC5A, ITGB3 and CCR5 genes and dengue severity in children. METHODS: A matched case-control study was conducted and 19 single nucleotide polymorphisms (SNPs) were investigated. FINDINGS: No associations were observed in single SNP analysis. However, when MBL2 SNPs were combined in haplotypes, the allele rs7095891G/rs1800450C/ rs1800451C/rs4935047A/rs930509G/rs2120131G/rs2099902C was significantly associated to risk of severe dengue under α = 0.05 (aOR = 4.02; p = 0.02). A second haplotype carrying rs4935047G and rs7095891G alleles was also associated to risk (aOR = 1.91; p = 0.04). MAIN CONCLUSIONS: This is the first study to demonstrate the association between MBL2 haplotypes and dengue severity in Brazilians including adjustment for genetic ancestry. These results reinforce the role of mannose binding lectin in immune response to DENV.

Guide for health professionals addressing oral care for individuals in oncological treatment based on scientific evidence.

OBJECTIVE: Oncological treatment can cause changes in the oral cavity compromising oral functions. The aim of the study was, based on a systematic review, to draft a guide directed at the team of health professionals involved in the oral care of oncological patients. METHODS: A systematic search of the literature was performed for articles published between 2000 and April 2017. Searches were made of electronic databases and hand search. The inclusion criteria were systematic reviews of randomized clinical trials (RCTs) and RCTs published in English, involving pediatric and adult oncological patients and focused on the prevention and treatment of oral complications as well as studies addressing the maintenance of oral health. Among the 1237 studies identified, 129 were pre-selected and 54 were selected to form the basis for the clinical guide. RESULTS: The studies analyzed stress the need for oral assessments as well as preventive and curative actions prior to oncological treatment. To minimize the severity of oral problems, the studies emphasize daily oral care, the treatment of xerostomia with saliva substitute and hydration, and low-level laser therapy, nystatin, acyclovir, respectively, for the prevention and treatment of oral mucositis, oral candidiasis, and infection by herpes simplex virus. Thus, the guide produced addresses oral assessments and professional and home care before, during, and after oncological treatment. CONCLUSION: The guide drafted has the function of assisting health professionals involved in the oral care of patients with cancer, enabling the prevention or treatment of oral complications stemming from oncological treatment.

Nonspecific hyperamylasemia: a case report.

CONTEXT: The elevation of serum amylase and lipase are generally associated with pancreatic diseases. However they can be associated with different pathologies unrelated with amylase and lipase. CASE REPORT: This paper aims to report a case of a patient diagnosed with nonspecific hyperamylasemia and warn of this possibility in the differentiation of hyperamylasemia. CONCLUSION: The correct diagnosis of silent hyperamylasemia is important in order to determine whether there is the risk of pancreatic disease or if we are just ahead of a benign hyperenzymemia.

Mass spectrometry molecular fingerprinting of mineral and synthetic lubricant oils.

The molecular composition of lubricating oils has a strong impact on how automotive engines function, but the techniques used to monitor the quality parameters of these oils only inspect their gross physical-chemical properties such as viscosity, color, and bulk spectroscopy profiles; hence, bad-quality, adulterated, or counterfeit oils are hard to detect. Herein, we investigated the ability of direct infusion electrospray ionization mass spectrometry (ESI-MS) to provide simple, rapid but characteristic fingerprint profiles for such oils of the mineral and synthetic types. After a simple aqueous extraction, ESI-MS analyses, particularly in the positive ion mode, did indeed show characteristic molecular markers with unique profiles, which were confirmed and more clearly visualized by partial least squares-discriminant analysis (PLS-DA). Nuclear magnetic resonance and Fourier transform infrared-attenuated total reflection spectroscopy were also tested for the bulk samples but showed nearly identical spectra, thus failing to reveal their distinct molecular composition and to differentiate the oil samples. To simulate adulteration, mixtures of mineral and synthetic oils were also analyzed by ESI(+)-MS, and additions as low as 1% of mineral oil to synthetic oil could be detected. The technique therefore offers a simple and fast but powerful tool to monitor the molecular composition of lubricant oils, particularly vias their more polar constituents.

Chromoblastomycosis: New Perspective on Adjuvant Treatment with Acitretin.

Chromoblastomycosis (CBM) is a neglected human disease, caused by different species of pigmented dematiaceous fungi that cause granulomatous and suppurative dermatosis. This infection is difficult to treat and there are limited therapeutic options, including terbinafine, itraconazole, and tioconazole. Classic treatment is administered for a long period of time, but some patients do not respond properly, and therefore, such therapeutic approaches possess low cure rates. Therefore, it is vital to develop new strategies for the treatment of CBM. In this regard, it has been observed that the association of immunomodulatory molecules such as glucan with therapy carried out with antifungal drugs improves cutaneous lesions in comparison to treatment with antifungal drugs alone, suggesting that drug association may be an interesting and significant approach to incorporate into CBM therapy. Thus, the aim of this work was to associate classical antifungal therapy with the adjuvants imiquimod and acitretin. In the present case, we reported a patient with extensive CBM caused by Fonsaecae pedrosoi, that affected an extensive area of the right leg, that was left without treatment for 11 years. He was treated with a classical combination of itraconazole and terbinafine via the oral route plus topical imiquimod and oral acitretin, as an adjuvant therapy. After five months of treatment, a significant regression of verrucous plaques was observed, suggesting that the use of these adjuvants combined with the classical antifungal drugs, intraconazole plus terbinafine, can reduce treatment time and rapidly improve the patient's quality of life. This result confirms that the use of coadjuvant drugs may be effective in the treatment of this infectious disease.

New Immunological Markers in Chromoblastomycosis-The Importance of PD-1 and PD-L1 Molecules in Human Infection.

The pathogenesis of chromoblastomycosis (CBM) is associated with Th2 and/or T regulatory immune responses, while resistance is associated with a Th1 response. However, even in the presence of IFN-γ, fungi persist in the lesions, and the reason for this persistence is unknown. To clarify the factors associated with pathogenesis, this study aimed to determine the polarization of the cellular immune response and the densities of cells that express markers of exhaustion in the skin of CBM patients. In the skin of patients with CBM, a moderate inflammatory infiltrate was observed, characterized primarily by the occurrence of histiocytes. Analysis of fungal density allowed us to divide patients into groups that exhibited low and high fungal densities; however, the intensity of the inflammatory response was not related to mycotic loads. Furthermore, patients with CBM exhibited a significant increase in the number of CD4+ and CD8+ cells associated with a high density of IL-10-, IL-17-, and IFN-γ-producing cells, indicating the presence of a chronic and mixed cellular immune response, which was also independent of fungal load. A significant increase in the number of PD-1+ and PD-L1+ cells was observed, which may be associated with the maintenance of the fungus in the skin and the progression of the disease.

Dynamics of chikungunya virus transmission in the first year after its introduction in Brazil: A cohort study in an urban community.

BACKGROUND: The first chikungunya virus (CHIKV) outbreaks during the modern scientific era were identified in the Americas in 2013, reaching high attack rates in Caribbean countries. However, few cohort studies have been performed to characterize the initial dynamics of CHIKV transmission in the New World. METHODOLOGY/PRINCIPAL FINDINGS: To describe the dynamics of CHIKV transmission shortly after its introduction in Brazil, we performed semi-annual serosurveys in a long-term community-based cohort of 652 participants aged ≥5 years in Salvador, Brazil, between Feb-Apr/2014 and Nov/2016-Feb/2017. CHIKV infections were detected using an IgG ELISA. Cumulative seroprevalence and seroincidence were estimated and spatial aggregation of cases was investigated. The first CHIKV infections were identified between Feb-Apr/2015 and Aug-Nov/2015 (incidence: 10.7%) and continued to be detected at low incidence in subsequent surveys (1.7% from Aug-Nov/2015 to Mar-May/2016 and 1.2% from Mar-May/2016 to Nov/206-Feb/2017). The cumulative seroprevalence in the last survey reached 13.3%. It was higher among those aged 30-44 and 45-59 years (16.1% and 15.6%, respectively), compared to younger (12.4% and 11.7% in <15 and 15-29 years, respectively) or older (10.3% in ≥60 years) age groups, but the differences were not statistically significant. The cumulative seroprevalence was similar between men (14.7%) and women (12.5%). Yet, among those aged 15-29 years, men were more often infected than women (18.1% vs. 7.4%, respectively, P = 0.01), while for those aged 30-44, a non-significant opposite trend was observed (9.3% vs. 19.0%, respectively, P = 0.12). Three spatial clusters of cases were detected in the study site and an increased likelihood of CHIKV infection was detected among participants who resided with someone with CHIKV IgG antibodies. CONCLUSIONS/SIGNIFICANCE: Unlike observations in other settings, the initial spread of CHIKV in this large urban center was limited and focal in certain areas, leaving a high proportion of the population susceptible to further outbreaks. Additional investigations are needed to elucidate the factors driving CHIKV spread dynamics, including understanding differences with respect to dengue and Zika viruses, in order to guide prevention and control strategies for coping with future outbreaks.

Skeletal Stem/Progenitor Cells in Periosteum and Skeletal Muscle Share a Common Molecular Response to Bone Injury.

Bone regeneration involves skeletal stem/progenitor cells (SSPCs) recruited from bone marrow, periosteum, and adjacent skeletal muscle. To achieve bone reconstitution after injury, a coordinated cellular and molecular response is required from these cell populations. Here, we show that SSPCs from periosteum and skeletal muscle are enriched in osteochondral progenitors, and more efficiently contribute to endochondral ossification during fracture repair as compared to bone-marrow stromal cells. Single-cell RNA sequencing (RNAseq) analyses of periosteal cells reveal the cellular heterogeneity of periosteum at steady state and in response to bone fracture. Upon fracture, both periosteal and skeletal muscle SSPCs transition from a stem/progenitor to a fibrogenic state prior to chondrogenesis. This common activation pattern in periosteum and skeletal muscle SSPCs is mediated by bone morphogenetic protein (BMP) signaling. Functionally, Bmpr1a gene inactivation in platelet-derived growth factor receptor alpha (Pdgfra)-derived SSPCs impairs bone healing and decreases SSPC proliferation, migration, and osteochondral differentiation. These results uncover a coordinated molecular program driving SSPC activation in periosteum and skeletal muscle toward endochondral ossification during bone regeneration. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Endophytic Trichoderma strains isolated from forest species of the Cerrado-Caatinga ecotone are potential biocontrol agents against crop pathogenic fungi.

The indiscriminate use of chemical pesticides increasingly harms the health of living beings and the environment. Thus, biological control carried out by microorganisms has gained prominence, since it consists of an environmentally friendly alternative to the use of pesticides for controlling plant diseases. Herein, we evaluated the potential role of endophytic Trichoderma strains isolated from forest species of the Cerrado-Caatinga ecotone as biological control agents of crop pathogenic fungi. Nineteen Trichoderma strains were used to assess the antagonistic activity by in vitro bioassays against the plant pathogens Colletotrichum truncatum, Lasiodiplodia theobromae, Macrophomina phaseolina, and Sclerotium delphinii isolated from soybean, cacao, fava bean, and black pepper crops, respectively. All Trichoderma strains demonstrated inhibitory activity on pathogen mycelial growth, with maximum percent inhibition of 70% against C. truncatum, 78% against L. theobromae, 78% against M. phaseolina, and 69% against S. delphinii. Crude methanol extracts (0.5 to 2.0 mg mL-1) of Trichoderma strains were able to inhibit the growth of C. truncatum, except Trichoderma sp. T3 (UFPIT06) and T. orientale (UFPIT09 and UFPIT17) at 0.5 mg mL-1, indicating that the endophytes employ a biocontrol mechanism related to antibiosis, together with multiple mechanisms. Discriminant metabolites of Trichoderma extracts were unveiled by liquid chromatography-tandem mass spectrometry-based metabolomics combined with principal component analysis (PCA), which included antifungal metabolites and molecules with other bioactivities. These results highlight the biocontrol potential of Trichoderma strains isolated from the Cerrado-Caatinga ecotone against crop pathogenic fungi, providing support for ongoing research on disease control in agriculture.

Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1.

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.

Cone-beam computed tomography artifacts in the presence of dental implants and associated factors: an integrative review.

PURPOSE: This study was conducted to review the literature regarding the types of cone-beam computed tomography (CBCT) artifacts around dental implants and the factors that influence their formation. MATERIALS AND METHODS: A search strategy was carried out in the PubMed, Embase, and Scopus databases to identify published between 2010 and 2020, and 9 studies were selected. The implants included 306 titanium, titanium-zirconium, and zirconia implants, as well as 5 titanium cylinders. RESULTS: The artifacts around the implants were the beam-hardening artifact, the streaking artifact, and band-like radiolucent areas. Some factors that influenced the formation of artifacts were the implant material, bone type, evaluated regions, distance, type of CBCT, field of view (FOV) size, milliamperage, peak kilovoltage (kVp), and voxel size. The beam-hardening artifact was the most widely reported, and it was minimized in protocols with a smaller FOV, larger voxels, and higher kVp. CONCLUSION: The risk and benefit of these protocols in individuals with dental implants must be considered, and clinical examinations and complementary radiographs play an essential role in implantology.

Acute-Phase Levels of CXCL8 as Risk Factor for Chronic Arthralgia Following Chikungunya Virus Infection.

The immunopathogenesis of chikungunya virus (CHIKV) infection and the role of acute-phase immune response on joint pain persistence is not fully understood. We investigated the profile of serum chemokine and cytokine in CHIKV-infected patients with acute disease, compared the levels of these biomarkers to those of patients with other acute febrile diseases (OAFD) and healthy controls (HC), and evaluated their role as predictors of chronic arthralgia development. Chemokines and cytokines were measured by flow Cytometric Bead Array. Patients with CHIKV infection were further categorized according to duration of arthralgia (≤ 3 months vs >3 months), presence of anti-CHIKV IgM at acute-phase sample, and number of days of symptoms at sample collection (1 vs 2-3 vs ≥4). Patients with acute CHIKV infection had significantly higher levels of CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1ß, IL-6, IL-12, and IL-10 as compared to HC. CCL2, CCL5, and CXCL10 levels were also significantly higher in patients with CHIKV infection compared to patients with OAFD. Patients whose arthralgia lasted > 3 months had increased CXCL8 levels compared to patients whose arthralgia did not (p<0.05). Multivariable analyses further indicated that high levels of CXCL8 and female sex were associated with arthralgia lasting >3 months. Patients with chikungunya and OAFD had similar cytokine kinetics for IL-1ß, IL-12, TNF, IFN-γ, IL-2, and IL-4, although the levels were lower for CHIKV patients. This study suggests that chemokines may have an important role in the immunopathogenesis of chronic chikungunya-related arthralgia.

Activation of an Effective Immune Response after Yellow Fever Vaccination Is Associated with the Genetic Background and Early Response of IFN-γ and CLEC5A.

The yellow fever vaccine (YF17DD) is highly effective with a single injection conferring protection for at least 10 years. The YF17DD induces polyvalent responses, with a TH1/TH2 CD4+ profile, robust T CD8+ responses, and synthesis of interferon-gamma (IFN-γ), culminating in high titers of neutralizing antibodies. Furthermore, C-type lectin domain containing 5A (CLEC5A) has been implicated in innate outcomes in other flaviviral infections. Here, we conducted a follow-up study in volunteers immunized with YF17DD, investigating the humoral response, cellular phenotypes, gene expression, and single nucleotide polymorphisms (SNPs) of IFNG and CLEC5A, to clarify the role of these factors in early response after vaccination. Activation of CLEC5A+ monocytes occurred five days after vaccination (DAV). Following, seven DAV data showed activation of CD4+ and CD8+T cells together with early positive correlations between type II IFN and genes of innate antiviral response (STAT1, STAT2, IRF7, IRF9, OAS1, and RNASEL) as well as antibody levels. Furthermore, individuals with genotypes rs2430561 AT/AA, rs2069718 AG/AA (IFNG), and rs13237944 AC/AA (CLEC5A), exhibited higher expression of IFNG and CLEC5A, respectively. Together, we demonstrated that early IFN-γ and CLEC5A responses, associated with rs2430561, rs2069718, and rs13237944 genotypes, may be key mechanisms in the long-lasting immunity elicited by YF17DD.

Stevens-Johnson syndrome and toxic epidermal necrolysis - retrospective review of cases in a high complexity hospital in Brazil.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by epidermal necrosis, mostly caused by drugs. Despite the rarity of these conditions, morbidity and mortality are high (even in previously healthy patients), and they may be associated with permanent sequelae. METHODS: A retrospective study conducted at a quaternary hospital in Brazil in a period of 10 years. RESULTS: The sample was composed by 41 patients with SJS, SJS/TEN, and TEN confirmed by skin biopsy. Antibiotics and anticonvulsants were the most frequently implied drug classes, and phenytoin was the most important individual culprit drug. In this study, 12.2% of the patients had sequelae, being ophthalmological lesions the most common and one case of a newly described hearing loss. The mortality rate was 16.7% in patients with TEN. CONCLUSIONS: This study describes the largest Latin American case series of SJS and TEN with the diagnosis proven by skin biopsy and adds important data regarding the profile of the disease in Brazil. It also describes a novel sequelae of hearing loss.

FGFR3 in Periosteal Cells Drives Cartilage-to-Bone Transformation in Bone Repair.

Most organs and tissues in the body, including bone, can repair after an injury due to the activation of endogenous adult stem/progenitor cells to replace the damaged tissue. Inherent dysfunctions of the endogenous stem/progenitor cells in skeletal repair disorders are still poorly understood. Here, we report that Fgfr3Y637C/+ over-activating mutation in Prx1-derived skeletal stem/progenitor cells leads to failure of fracture consolidation. We show that periosteal cells (PCs) carrying the Fgfr3Y637C/+ mutation can engage in osteogenic and chondrogenic lineages, but following transplantation do not undergo terminal chondrocyte hypertrophy and transformation into bone causing pseudarthrosis. Instead, Prx1Cre;Fgfr3Y637C/+ PCs give rise to fibrocartilage and fibrosis. Conversely, wild-type PCs transplanted at the fracture site of Prx1Cre;Fgfr3Y637C/+ mice allow hypertrophic cartilage transition to bone and permit fracture consolidation. The results thus highlight cartilage-to-bone transformation as a necessary step for bone repair and FGFR3 signaling within PCs as a key regulator of this transformation.