RESUMO
Evolution is replete with reuse of genes in different contexts, leading to multifunctional roles of signaling factors during development. Here, we explore osteoclast regulation during skeletal development through analysis of colony-stimulating factor 1 receptor (csf1r) function in the zebrafish. A primary role of Csf1r signaling is to regulate the proliferation, differentiation and function of myelomonocytic cells, including osteoclasts. We demonstrate the retention of two functional paralogues of csf1r in zebrafish. Mutant analysis indicates that the paralogues have shared, non-redundant roles in regulating osteoclast activity during the formation of the adult skeleton. csf1ra, however, has adopted unique roles in pigment cell patterning not seen in the second paralogue. We identify a unique noncoding element within csf1ra of fishes that is sufficient for controlling gene expression in pigment cells during development. As a role for Csf1r signaling in pigmentation is not observed in mammals or birds, it is likely that the overlapping roles of the two paralogues released functional constraints on csf1ra, allowing the signaling capacity of Csf1r to serve a novel function in the evolution of pigment pattern in fishes.
Assuntos
Desenvolvimento Embrionário , Proteínas Tirosina Quinases/metabolismo , Homologia de Sequência de Aminoácidos , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Osso e Ossos/metabolismo , Dentição , Desenvolvimento Embrionário/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Modelos Biológicos , Mutação/genética , Fenótipo , Pigmentação/genética , Proteínas Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
PURPOSE OF REVIEW: To provide a comprehensive overview of the inflammatory response following anterior cruciate ligament (ACL) injury and to highlight the relationship between specialized pro-resolving mediators (SPMs) and inflammatory joint conditions, emphasizing the therapeutic potential of modulating the post-injury resolution of inflammation to prevent posttraumatic osteoarthritis (PTOA). RECENT FINDINGS: The inflammatory response triggered after joint injuries such as ACL tear plays a critical role in posttraumatic osteoarthritis development. Inflammation is a necessary process for tissue healing, but unresolved or overactivated inflammation can lead to chronic diseases. SPMs, a family of lipid molecules derived from essential fatty acids, have emerged as active players in the resolution of inflammation and tissue repair. While their role in other inflammatory conditions has been studied, their relationship with PTOA remains underexplored. Proinflammatory mediators contribute to cartilage degradation and PTOA pathogenesis, while anti-inflammatory and pro-resolving mediators may have chondroprotective effects. Therapies aimed at suppressing inflammation in PTOA have limitations, as inflammation is crucial for tissue healing. SPMs offer a pro-resolving response without causing immunosuppression, making them a promising therapeutic option. The known onset date of PTOA makes it amenable to early interventions, and activating pro-resolving pathways may provide new possibilities for preventing PTOA progression. Harnessing the pro-resolving potential of SPMs may hold promise for preventing PTOA and restoring tissue homeostasis and function after joint injuries.
Assuntos
Lesões do Ligamento Cruzado Anterior , Osteoartrite , Humanos , Osteoartrite/tratamento farmacológico , Osteoartrite/etiologia , Inflamação/metabolismo , Lesões do Ligamento Cruzado Anterior/complicações , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/uso terapêuticoRESUMO
Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mø toward a reparative phenotype, and enhanced Mø clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis.
Assuntos
Artrite Experimental , Artrite Reumatoide , Interleucinas , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Proteínas de Transporte , Inflamação , Interleucinas/metabolismo , Camundongos , Camundongos Knockout , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Membrana Sinovial/metabolismoRESUMO
Public health travel restrictions (PHTR) are crucial measures during communicable disease outbreaks to prevent transmission during commercial airline travel and mitigate cross-border importation and spread. We evaluated PHTR implementation for US citizens on the Diamond Princess during its coronavirus disease (COVID-19) outbreak in Japan in February 2020 to explore how PHTR reduced importation of COVID-19 to the United States during the early phase of disease containment. Using PHTR required substantial collaboration among the US Centers for Disease Control and Prevention, other US government agencies, the cruise line, and public health authorities in Japan. Original US PHTR removal criteria were modified to reflect international testing protocols and enable removal of PHTR for persons who recovered from illness. The impact of PHTR on epidemic trajectory depends on the risk for transmission during travel and geographic spread of disease. Lessons learned from the Diamond Princess outbreak provide critical information for future PHTR use.
Assuntos
COVID-19/transmissão , Doenças Transmissíveis Importadas/prevenção & controle , Surtos de Doenças/prevenção & controle , Quarentena , Viagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Governo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Navios , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by Trip11) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly tissue specific, mainly affecting cartilage development. Bone development is also abnormal, but as chondrogenesis and osteogenesis are closely coupled, this could be a secondary consequence of the cartilage defect. A possible explanation for the tissue specificity of ACG1A is that cartilage and bone are highly secretory tissues with a high use of the membrane trafficking machinery. The perinatal lethality of ACG1A prevents investigating this hypothesis. We therefore generated mice with conditional Trip11 knockout alleles and inactivated Trip11 in chondrocytes, osteoblasts, osteoclasts and pancreas acinar cells, all highly secretory cell types. We discovered that the ACG1A skeletal phenotype is solely due to absence of GMAP-210 in chondrocytes. Mice lacking GMAP-210 in osteoblasts, osteoclasts and acinar cells were normal. When we inactivated Trip11 in primary chondrocyte cultures, GMAP-210 deficiency affected trafficking of a subset of chondrocyte-expressed proteins rather than globally impairing membrane trafficking. Thus, GMAP-210 is essential for trafficking specific cargoes in chondrocytes but is dispensable in other highly secretory cells.
Assuntos
Acondroplasia , Alelos , Desenvolvimento Ósseo/genética , Cartilagem , Fenótipo , Acondroplasia/genética , Acondroplasia/metabolismo , Acondroplasia/patologia , Animais , Transporte Biológico Ativo/genética , Cartilagem/anormalidades , Cartilagem/metabolismo , Cartilagem/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Proteínas do Citoesqueleto , Camundongos , Camundongos Knockout , Proteínas Nucleares/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologiaRESUMO
An estimated 30 million passengers are transported on 272 cruise ships worldwide each year* (1). Cruise ships bring diverse populations into proximity for many days, facilitating transmission of respiratory illness (2). SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) was first identified in Wuhan, China, in December 2019 and has since spread worldwide to at least 187 countries and territories. Widespread COVID-19 transmission on cruise ships has been reported as well (3). Passengers on certain cruise ship voyages might be aged ≥65 years, which places them at greater risk for severe consequences of SARS-CoV-2 infection (4). During February-March 2020, COVID-19 outbreaks associated with three cruise ship voyages have caused more than 800 laboratory-confirmed cases among passengers and crew, including 10 deaths. Transmission occurred across multiple voyages of several ships. This report describes public health responses to COVID-19 outbreaks on these ships. COVID-19 on cruise ships poses a risk for rapid spread of disease, causing outbreaks in a vulnerable population, and aggressive efforts are required to contain spread. All persons should defer all cruise travel worldwide during the COVID-19 pandemic.
Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Surtos de Doenças/prevenção & controle , Saúde Global/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Prática de Saúde Pública , Navios , Doença Relacionada a Viagens , Adulto , Idoso , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Fatores de Risco , SARS-CoV-2 , Estados Unidos/epidemiologiaRESUMO
Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth.
Assuntos
Desenvolvimento Ósseo , Osso e Ossos/metabolismo , Microbioma Gastrointestinal , Fator de Crescimento Insulin-Like I/metabolismo , Tecido Adiposo/metabolismo , Animais , Ácidos Graxos Voláteis/metabolismo , Feminino , Fígado/metabolismo , Masculino , Camundongos , Osteogênese , Organismos Livres de Patógenos EspecíficosRESUMO
Long-term effects of breastfeeding on maternal bone are not fully understood. Excessive maternal bone loss stimulated by serotonin signaling during lactation may increase bone fragility later in life. We hypothesized that inhibiting nonneuronal serotonin activity by feeding a small-molecule inhibitor of the rate-limiting enzyme in serotonin synthesis [tryptophan hydroxylase 1 (TPH1)] would preserve maternal bone postweaning without affecting neonatal bone. Chow supplemented with the small-molecule TPH1 inhibitor LP778902 (~100 mg/kg) or control chow was fed to C57BL/6 dams throughout pregnancy and lactation, and blood was collected on days 1 and 21 of lactation. Dams returned to a common diet postweaning and were aged to 3 or 9 mo postweaning. Pups were euthanized at weaning. The effect of TPH1 inhibition on dam and pup femoral bone was determined by micro-computed tomography. Peripartum dietary supplementation with LP778902 decreased maternal serum serotonin concentrations ( P = 0.0007) and reduced bone turnover, indicated by serum NH2-terminal propeptide of type I collagen ( P = 0.01) and COOH-terminal collagen cross-links ( P = 0.02) concentrations, on day 21 of lactation. Repressed bone turnover from TPH1 inhibition was not associated with structural changes in maternal femur at 3 or 9 mo postweaning. By contrast, neonates exposed to peripartum LP778902 demonstrated differences in trabecular and cortical femoral bone compared with pups from control dams, with fewer ( P = 0.02) and thinner ( P = 0.001) trabeculae as well as increased trabecular spacing ( P = 0.04). Additionally, cortical porosity was increased ( P = 0.007) and cortical tissue mineral density was decreased ( P = 0.005) in pups of LP778902-treated dams. Small-molecule TPH1 inhibitors should be carefully considered in pregnant and lactating women, given potential risks to neonatal bone development.
Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Fêmur/diagnóstico por imagem , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Serotonina/sangue , Triptofano Hidroxilase/antagonistas & inibidores , Animais , Biomarcadores/sangue , Colágeno Tipo I/sangue , Suplementos Nutricionais , Feminino , Lactação/efeitos dos fármacos , Camundongos , Peptídeos/sangue , Gravidez , Microtomografia por Raio-XAssuntos
Doenças do Pé/patologia , Pé/diagnóstico por imagem , Fraturas Ósseas/etiologia , Hipofosfatemia/etiologia , Mesenquimoma/diagnóstico , Osteomalacia/diagnóstico , Síndromes Paraneoplásicas/diagnóstico , Doenças Ósseas Metabólicas , Calcitriol/uso terapêutico , Feminino , Pé/patologia , Doenças do Pé/complicações , Doenças do Pé/diagnóstico por imagem , Humanos , Hipocalcemia/etiologia , Imageamento por Ressonância Magnética , Mesenquimoma/complicações , Mesenquimoma/patologia , Pessoa de Meia-Idade , Osteomalacia/etiologia , Fosfatos/metabolismo , Fosfatos/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
Microbiota and their hosts have coevolved for millions of years. Microbiota are not only critical for optimal development of the host under normal physiological growth, but also important to ensure proper host development during nutrient scarcity or disease conditions. A large body of research has begun to detail the mechanism(s) of how microbiota cooperate with the host to maintain optimal health status. One crucial host pathway recently demonstrated to be modulated by microbiota is that of the growth factor insulin like growth factor 1 (IGF-1). Gut microbiota are capable of dynamically modulating circulating IGF-1 in the host, with the majority of data suggesting that microbiota induce host IGF-1 synthesis to influence growth. Microbiota-derived metabolites such as short chain fatty acids are sufficient to induce IGF-1. Whether microbiota induction of IGF-1 is mediated by the difference in growth hormone expression or the host sensitivity to growth hormone is still under investigation. This review summarizes the current data detailing the interaction between gut microbiota, IGF-1 and host development.
Assuntos
Microbioma Gastrointestinal/fisiologia , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Microbiota/fisiologia , Animais , Humanos , Proteínas Recombinantes/metabolismoRESUMO
PURPOSE OF REVIEW: The gut microbiota can be considered a hidden organ that plays essential roles in host homeostasis. Exploration of the effects of microbiota on bone has just begun. Complimentary studies using germ-free mice, antibiotic, and probiotic treatments reveal a complicated relationship between microbiota and bone. Here, we review recent reports addressing the effect of gut microbiota on bone health, discuss potential reasons for discrepant findings, and explore potential mechanisms for these effects. RECENT FINDINGS: Manipulation of microbiota by colonization of germ-free mice, antibiotics, or probiotic supplementation significantly alters bone remodeling, bone development and growth, as well as bone mechanical strength. Different experimental models reveal context-dependent effects of gut microbiota on bone. By examining phenotypic effects, experimental context, and proposed mechanisms, revealed by recent reports, we hope to provide comprehensive and fresh insights into the many facets of microbiota and bone interactions.
Assuntos
Desenvolvimento Ósseo/fisiologia , Remodelação Óssea/fisiologia , Osso e Ossos/metabolismo , Microbioma Gastrointestinal/fisiologia , Animais , Antibacterianos , Fenômenos Biomecânicos , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Vida Livre de Germes , Humanos , Camundongos , Modelos Animais , Osteoporose Pós-Menopausa/metabolismo , ProbióticosRESUMO
Recent advances have dramatically increased our understanding of how organ systems interact. This has been especially true for immunology and bone biology, where the term "osteoimmunology" was coined to capture this relationship. The importance of the microbiome to the immune system has also emerged as a driver of health and disease. It makes sense therefore to ask the question: how does the intestinal microbiome influence bone biology and does dysbiosis promote bone disease? Surprisingly, few studies have analyzed this connection. A broader interpretation of this question reveals many mechanisms whereby the microbiome may affect bone cells. These include effects of the microbiome on immune cells, including myeloid progenitors and Th17 cells, as well as steroid hormones, fatty acids, serotonin and vitamin D. As mechanistic interactions of the microbiome and skeletal system are revealed within and without the immune system, novel strategies to optimize skeletal fitness may emerge.
Assuntos
Corticosteroides/metabolismo , Osso e Ossos/imunologia , Citocinas/imunologia , Microbioma Gastrointestinal/imunologia , Hormônios Esteroides Gonadais/metabolismo , Osteoblastos/imunologia , Osteoclastos/imunologia , Células Th17/imunologia , Animais , Reabsorção Óssea/imunologia , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Humanos , Intestinos/imunologia , Intestinos/microbiologia , Camundongos , Células Mieloides/imunologia , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/imunologia , Linfócitos T/imunologiaRESUMO
Missense mutations that reduce or abrogate myeloid cell expression of the F-BAR domain protein, proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), lead to autoinflammatory disease involving extramedullary hematopoiesis, skin and bone lesions. However, little is known about how PSTPIP2 regulates osteoclast development. Here we examined how PSTPIP2 deficiency causes osteopenia and bone lesions, using the mouse PSTPIP2 mutations, cmo, which fails to express PSTPIP2 and Lupo, in which PSTPIP2 is dysfunctional. In both models, serum levels of the pro-osteoclastogenic factor, MIP-1α, were elevated and CSF-1 receptor (CSF-1R)-dependent production of MIP-1α by macrophages was increased. Treatment of cmo mice with a dual specificity CSF-1R and c-Kit inhibitor, PLX3397, decreased circulating MIP-1α and ameliorated the extramedullary hematopoiesis, inflammation, and osteopenia, demonstrating that aberrant myelopoiesis drives disease. Purified osteoclast precursors from PSTPIP2-deficient mice exhibit increased osteoclastogenesis in vitro and were used to probe the structural requirements for PSTPIP2 suppression of osteoclast development. PSTPIP2 tyrosine phosphorylation and a functional F-BAR domain were essential for PSTPIP2 inhibition of TRAP expression and osteoclast precursor fusion, whereas interaction with PEST-type phosphatases was only required for suppression of TRAP expression. Thus, PSTPIP2 acts as a negative feedback regulator of CSF-1R signaling to suppress inflammation and osteoclastogenesis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Doenças Ósseas Metabólicas/etiologia , Diferenciação Celular , Quimiocina CCL3/sangue , Proteínas do Citoesqueleto/fisiologia , Osteoclastos/patologia , Osteomielite/etiologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Animais , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Dicroísmo Circular , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Knockout , Mutação/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Osteoclastos/metabolismo , Osteomielite/metabolismo , Osteomielite/patologia , Fosforilação/efeitos dos fármacos , Ligante RANK/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Tirosina/metabolismoRESUMO
The immune system and bone are intimately linked with significant physical and functionally related interactions. The innate immune system functions as an immediate response system to initiate protections against local challenges such as pathogens and cellular damage. Bone is a very specific microenvironment, in which infectious attack is less common but repair and regeneration are ongoing and important functions. Thus, in the bone the primary goal of innate immune and bone interactions is to maintain tissue integrity. Innate immune signals are critical for removal of damaged and apoptotic cells and to stimulate normal tissue repair and regeneration. In this review we focus on the innate immune mechanisms that function to regulate bone homeostasis.
Assuntos
Remodelação Óssea/imunologia , Osso e Ossos/imunologia , Imunidade Inata/imunologia , Osteoclastos/fisiologia , Apoptose/imunologia , Autofagia/imunologia , Osso e Ossos/fisiologia , Homeostase/imunologia , HumanosRESUMO
Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is known to play multiple biological roles by regulating transcriptional expression, RNA splicing, RNA stability, and chromatin structure in a tissue-dependent manner. The role of hnRNPU in skeletal muscle development and maintenance has not been previously evaluated. In this study, skeletal muscle specific hnRNPU knock out mice is utilized and evaluated skeletal muscle mass and immune cell infiltration through development. By 4 weeks, muscle-specific hnRNPU knockout mice revealed Ly6C+ monocyte infiltration into skeletal muscle, which preceded muscle atrophy. Canonical NF-kB signaling is activated in a myofiber-autonomous manner with hnRNPU repression. Inducible hnRNPU skeletal muscle knockout mice further demonstrated that deletion of hnRNPU in adulthood is sufficient to cause muscle atrophy, suggesting that hnRNPU's role in muscle maintenance is not during development alone. Treatment with salirasib, to inhibit proliferation of immune cells, prevents muscle atrophy in muscle-specific hnRNPU knock out mice, indicating that immune cell infiltration plays causal role in muscle atrophy of hnRNPU knock out mice. Overall, the findings suggest that loss of hnRNPU triggers muscle inflammation and activates NF-κB signaling in a cell-autonomous manner, culminating in muscle atrophy.
Assuntos
Camundongos Knockout , Músculo Esquelético , Atrofia Muscular , NF-kappa B , Transdução de Sinais , Animais , Camundongos , Antígenos Ly , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/genética , NF-kappa B/metabolismo , NF-kappa B/genéticaRESUMO
Objectives: Rare metabolic bone diseases can present with symptoms mimicking more common rheumatological conditions including spondyloarthritis, osteoarthritis, and fibromyalgia. Increasing awareness of these rare diseases within the rheumatology community is vital to ensure that affected patients are diagnosed and appropriately treated. The literature includes several reports of tumour-induced osteomalacia initially diagnosed as rheumatic disease, but other rare diseases such as X-linked hypophosphatemia (XLH) and hypophosphatasia (HPP) also deserve attention. Here, we describe two cases of adult patients incorrectly diagnosed with ankylosing spondylitis and osteoarthritis who, upon referral to a metabolic bone disease specialist, were subsequently diagnosed with XLH and HPP, respectively, profoundly altering their management. Methods: The cases were collected from Brigham and Women's Hospital, Boston, MA, USA, and Vanderbilt University Medical Center, Nashville, TN, USA. Results: Details of the patients' respective medical and family histories are presented, and the clinical and biochemical investigations undertaken to reach the correct diagnoses are described. Conclusion: Rheumatologists should be encouraged to think beyond common rheumatological diseases when faced with symptoms such as bone pain, muscle pain, and stiffness, especially when accompanied by manifestations including atraumatic fractures, poor dentition, and hearing loss. In cases where one of these rare diseases is suspected, referral to a metabolic bone disease specialist for confirmation of diagnosis is encouraged as effective treatment options have recently become available.
RESUMO
BACKGROUND: Reduced viability in the deepest zones of osteochondral allografts (OCAs) can weaken the subchondral interface, potentially increasing the risk of failure. This reduction may result from nutritional imbalances due to uneven media distribution or interference from bone marrow elements. PURPOSE: To investigate whether culturing OCAs using a rotary shaker or removing the bone marrow elements would increase graft cellular viability. STUDY DESIGN: Controlled laboratory study. METHODS: Bovine osteochondral explants were stored for 28 days at 4°C under 3 different conditions (n = 6 explants per group): static (control group), rotary shaker at 150 rpm (shaker group), and static after removal of bone marrow elements using a Waterpik device (Waterpik group). Chondrocyte viability was assessed using live/dead staining across the entire tissue and in each zone (superficial, middle, deep). Subchondral bone viability was assessed using TUNEL (terminal deoxynucleotidal transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling) staining to detect apoptotic cells. RESULTS: Both shaker (64.2%; P = .010) and Waterpik (65.6%; P = .005) conditions showed significantly higher chondrocyte viability compared with control (49.8%). When samples were analyzed by zone, the shaker and Waterpik groups displayed higher cellular viability at the middle zone (shaker = 60.6%, P < .001; Waterpik = 56.1%, P < .001) and deep zone (shaker = 63.1%, P = .018; Waterpik = 61.5%, P = .025) than the control group (25.6% at middle zone; 32.8% at deep zone). Additionally, shaker (56.7%; P = .018) and Waterpik (51.4%; P = .007) groups demonstrated a lower percentage of apoptotic cells in subchondral bone compared with control (88.0%). No significant differences were observed between the shaker and Waterpik groups in any of the analyses. CONCLUSION: Both rotary shaking and removal of bone marrow elements during storage of osteochondral explants led to higher chondrocyte viability at the middle and deep zones of the graft compared with the static storage condition. Enhancing nutrition delivery to the graft could improve its quality, potentially improving outcomes of OCA transplantation. CLINICAL RELEVANCE: The use of a rotary shaker or the removal of bone marrow elements may significantly improve the culture conditions, increasing graft viability and integrity after OCA storage.
Assuntos
Sobrevivência Celular , Condrócitos , Animais , Bovinos , Medula Óssea , Cartilagem Articular/fisiologia , Técnicas de Cultura de TecidosRESUMO
Widely varying prevalence of vitamin D deficiency has been reported in patients presenting for total knee arthroplasty (TKA). The primary aim of this study was to determine vitamin D levels in TKA patients and to compare to patients already routinely evaluated for vitamin D levels, patients with fragility fractures of the distal radius (DRF). There is significant overlap between patients presenting for TKA and with DRF, both in terms of medical comorbidities and overall health status, making these populations suitable comparative cohorts. Wefound that all patients presenting for TKA consultation had vitamin D insufficiency and 33% had vitamin D deficiency, compared to only 37% and 14% in the DRF cohort, a patient population routinely evaluated for vitamin D due to the high risk of deficiency. Furthermore, patients with DRF had higher levels of vitamin D before (38 ± 16 vs. 23 ± 5) and after vitamin D supplementation (39 ± 17 vs. 33 ± 10), suggesting that patients presenting for TKA are at even higher risk of vitamin D insufficiency than patients presenting with DRF. Reassuringly, supplementation successfully corrected 39.0% and 55.8% of patients in the DRF and TKA cohorts, respectively.
Assuntos
Artroplastia do Joelho , Deficiência de Vitamina D , Humanos , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Artroplastia do Joelho/efeitos adversos , Idoso , Feminino , Masculino , Pessoa de Meia-Idade , Vitamina D/sangue , Idoso de 80 Anos ou maisRESUMO
Cartilage tissue exhibits early degenerative changes with onset of osteoarthritis (OA). Early diagnosis is critical as there is only a narrow time window during which therapeutic intervention can reverse disease progression. Computed tomography (CT) has been considered for cartilage imaging as a tool for early OA diagnosis by introducing radio-opaque contrast agents like ioxaglate (IOX) into the joint. IOX, however, is anionic and thus repelled by negatively charged cartilage glycosaminoglycans (GAGs) that hinders its intra-tissue penetration and partitioning, resulting in poor CT attenuation. This is further complicated by its short intra-tissue residence time owing to rapid clearance from joints, which necessitates high doses causing toxicity concerns. Here we engineer optimally charged cationic contrast agents based on cartilage negative fixed charge density by conjugating cartilage targeting a cationic peptide carrier (CPC) and multi-arm avidin nanoconstruct (mAv) to IOX, such that they can penetrate through the full thickness of cartilage within 6 h using electrostatic interactions and elicit similar CT signal with about 40× lower dose compared to anionic IOX. Their partitioning and distribution correlate strongly with spatial GAG distribution within healthy and early- to late-stage arthritic bovine cartilage tissues at 50-100× lower doses than other cationic contrast agents used in the current literature. The use of contrast agents at low concentrations also allowed for delineation of cartilage from subchondral bone as well as other soft tissues in rat tibial joints. These contrast agents are safe to use at current doses, making CT a viable imaging modality for early detection of OA and staging of its severity.