ABSTRACT
Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.
Subject(s)
Arthritis, Rheumatoid/genetics , Drosophila Proteins/genetics , Muscle, Skeletal/metabolism , Smoothened Receptor/genetics , Ubiquitin-Protein Ligases/genetics , Animals , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Cartilage/growth & development , Cartilage/metabolism , Cartilage/pathology , Chondrocytes/metabolism , Disease Models, Animal , Drosophila melanogaster/genetics , Hedgehog Proteins/genetics , Homeostasis/genetics , Humans , Knee Joint/metabolism , Knee Joint/pathology , Mice , Muscle, Skeletal/pathology , Osteogenesis/genetics , Signal Transduction/genetics , Tendons/metabolism , Tendons/pathologyABSTRACT
This review highlights the essential role of Hedgehog (Hh) signalling in the developmental steps of temporomandibular joint (TMJ) formation. We review evidence for intra- and potentially inter-tissue Hh signaling as well as Glioma-Associated Oncogene Homolog (GLI) dependent and independent functions. Morphogenesis and maturation of the TMJ's individual components and the general landscape of Hh signalling is also covered. Comparison of the appendicular knee and axial TMJ also reveals interesting differences and similarities in their mechanisms of development, chondrogenesis and reliance on Hh signalling.
ABSTRACT
OBJECTIVES: Patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) may be agraphic. The study aimed at characterizing agraphia in individuals with a P301L MAPT mutation. METHODS: Two pairs of siblings with FTDP-17 were longitudinally examined for agraphia in relation to language and cognitive deficits. RESULTS: All patients presented with dysexecutive agraphia. In addition, in the first pair of siblings one sibling demonstrated spatial agraphia with less pronounced allographic agraphia and the other sibling had aphasic agraphia. Aphasic agraphia was also present in one sibling from the second pair. CONCLUSION: Agraphia associated with FTDP-17 is very heterogeneous.
Subject(s)
Agraphia/diagnosis , Agraphia/genetics , Chromosomes, Human, Pair 17 , Frontotemporal Dementia/genetics , Parkinsonian Disorders/genetics , tau Proteins/genetics , Brain/pathology , Disease Progression , Female , Frontotemporal Dementia/pathology , Frontotemporal Dementia/psychology , Humans , Longitudinal Studies , Male , Middle Aged , Mutation , Parkinsonian Disorders/pathology , Parkinsonian Disorders/psychologyABSTRACT
Recent stressful life events (ASLE) are considered to be one of the factors precipitating suicidal behavior. They precede a suicide attempt in most cases and according to research occur more often during the month or week before the suicide attempt. Interpersonal events are most common. The article presents an analysis of ASLE timing and incidence of events from specific categories during the month preceding suicide attempt by drug overdose. 124 patients admitted to the hospital because of suicidal intoxication were included in the study. Data regarding ASLE were collected with the use of a structured interview. Majority of patients attempting suicide by drug overdose experience a stressful event during the month prior to the suicide attempt. Nearly 4 out of 10 study subjects experience a stressful event on the day of the attempt or on the preceding day. Most common events that occur during the month prior to the attempt and immediately before the attempt are interpersonal events and most of them are related to relationships with spouses or partners.
