For many years Canis familiaris, the domestic dog, has drawn particular interest as a model of osteoarthritis (OA). Here, we optimized the dog model of experimental OA induced by cranial cruciate ligament sectioning. The usefulness of noninvasive complementary outcome measures, such as gait analysis for the limb function and magnetic resonance imaging for structural changes, was demonstrated in this model. Relationships were established between the functional impairment and the severity of structural changes including the measurement of cartilage thinning. In the dog model of naturally occurring OA, excellent test-retest reliability was denoted for the measurement of the limb function. A criterion to identify clinically meaningful responders to therapy was determined for privately owned dogs undergoing clinical trials. In addition, the recording of accelerometer-based duration of locomotor activity showed strong and complementary agreement with the biomechanical limb function. The translation potential of these models to the human OA condition is underlined. A preclinical testing protocol which combines the dog model of experimental OA induced by cranial cruciate ligament transection and the Dog model of naturally occurring OA offers the opportunity to further investigate the structural and functional benefits of disease-modifying strategies. Ultimately, a better prediction of outcomes for human clinical trials would be brought.
Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2
SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis.
association; canine; disease; longevity; morphology; QTL
In dogs hip joint laxity that can lead to degenerative joint disease (DJD) is frequent and heritable, providing a genetic model for some aspects of the human disease. We have used Portuguese water dogs (PWDs) to identify Quantitative trait loci (QTLs) that regulate laxity in the hip joint.A population of 286 PWDs, each characterized by ca. 500 molecular genetic markers, was analyzed for subluxation of the hip joint as measured by the Norberg angle, a quantitative radiographic measure of laxity. A significant directed asymmetry was observed, such that greater laxity was observed in the left than the right hip. This asymmetry was not heritable. However, the average Norberg angle was highly heritable as were the Norberg angles of either the right or left hips. After correction for pedigree effects, two QTLs were identified using the metrics of the left and right hips as separate data sets. Both are on canine chromosome 1 (CFA1), separated by about 95 Mb. One QTL, associated with the SSR marker FH2524 was significant for the left, but not the right hip. The other, associated with FH2598, was significant for the right but not the left hip. For both QTLs, some extreme phenotypes were best explained by specific interactions between haplotypes.
quantitative trait loci (QTLs); dog; hip laxity; bilateral asymmetry; Norberg angle; Canine genetics; hip dysplasia
Magnetic resonance (MR) imaging is the preferred diagnostic tool to evaluate internal disorders of many joints in humans; however, the usefulness of MR imaging in the context of osteoarthritis, and joint disease in general, has yet to be characterized in veterinary medicine. The objective of this study was to assess the diagnostic accuracy of short-duration 3 Tesla MR imaging for the evaluation of cranial and caudal cruciate ligament, meniscal and cartilage damage, as well as the degree of osteoarthritis, in dogs affected by non-traumatic, naturally-occurring cranial cruciate ligament rupture (CCLR). Diagnoses made from MR images were compared to those made during surgical exploration. Twenty-one client-owned dogs were included in this study, and one experienced evaluator assessed all images.
All cranial cruciate ligaments were correctly identified as ruptured. With one exception, all caudal cruciate ligaments were correctly identified as intact. High sensitivities and specificities were obtained when diagnosing meniscal rupture. MR images revealed additional subclinical lesions in both the cranial and caudal cruciate ligaments and in the menisci. There was a “clear” statistical (kappa) agreement between the MR and the surgical findings for both cartilage damage and degree of osteoarthritis. However, the large 95% confidence intervals indicated that evaluation of cartilage damage and of degree of osteoarthritis is not clinically satisfactory.
The presence of cruciate ligament damage and meniscal tears could be accurately assessed using the MR images obtained with our protocol. However, in the case of meniscal evaluation, occasional misdiagnosis did occur. The presence of cartilage damage and the degree of osteoarthritis could not be properly evaluated.
Dog; Stifle; Cranial cruciate ligament; High-field MRI; Radiography
Polymorphism in genes of regulating enzymes, transporters and receptors of the neurotransmitters of the central nervous system have been associated with altered behaviour, and single nucleotide polymorphisms (SNPs) represent the most frequent type of genetic variation. The serotonin and dopamine signalling systems have a central influence on different behavioural phenotypes, both of invertebrates and vertebrates, and this study was undertaken in order to explore genetic variation that may be associated with variation in behaviour.
Single nucleotide polymorphisms in canine genes related to behaviour were identified by individually sequencing eight dogs (Canis familiaris) of different breeds. Eighteen genes from the dopamine and the serotonin systems were screened, revealing 34 SNPs distributed in 14 of the 18 selected genes. A total of 24,895 bp coding sequence was sequenced yielding an average frequency of one SNP per 732 bp (1/732). A total of 11 non-synonymous SNPs (nsSNPs), which may be involved in alteration of protein function, were detected. Of these 11 nsSNPs, six resulted in a substitution of amino acid residue with concomitant change in structural parameters.
We have identified a number of coding SNPs in behaviour-related genes, several of which change the amino acids of the proteins. Some of the canine SNPs exist in codons that are evolutionary conserved between five compared species, and predictions indicate that they may have a functional effect on the protein. The reported coding SNP frequency of the studied genes falls within the range of SNP frequencies reported earlier in the dog and other mammalian species. Novel SNPs are presented and the results show a significant genetic variation in expressed sequences in this group of genes. The results can contribute to an improved understanding of the genetics of behaviour.
Femoroacetabular impingement (FAI) is an established cause of osteoarthrosis of the hip. Surgery is intended to remove the cause of impingement with hip dislocation and resection of osseous prominences of the acetabular rim and of the femoral head-neck junction. Using the Merle d’Aubigné score and qualitative categories, recent studies suggest good to excellent outcomes in 75% to 80% of patients after open surgery with dislocation of the femoral head. Unsatisfactory outcome is mainly related to pain, located either in the area of the greater trochanter or in the groin. There are several reasons for persisting groin pain. Joint degeneration with joint space narrowing and/or osteophyte formation, insufficient correction of the acetabula, and femoral pathology are known factors for unsatisfactory outcome. Recently, intraarticular adhesions between the femoral neck and joint capsule have been identified as an additional cause of postoperative groin pain. The adhesions form between the joint capsule and the resected area on the femoral neck and may lead to soft tissue impingement. MR-arthrography is used for diagnosis and the adhesions can be treated successfully by arthroscopy. While arthroscopic resection improves outcome it is technically demanding. Avoiding the formation of adhesions is important and is perhaps best accomplished by passive motion exercises after the initial surgery.
Level of Evidence: Level V, expert opinion. See the Guidelines for Authors for a complete description of levels of evidence.
Hybrids such as maize (Zea mays) or domestic dog (Canis lupus familiaris) grow bigger and stronger than their parents. This is also true for allopolyploids such as wheat (Triticum spp.) or frog (i.e. Xenopus and Silurana) that contain two or more sets of chromosomes from different species. The phenomenon, known as hybrid vigor or heterosis, was systematically characterized by Charles Darwin (1876). The rediscovery of heterosis in maize a century ago has revolutionized plant and animal breeding and production. Although genetic models for heterosis have been rigorously tested, the molecular bases remain elusive. Recent studies have determined the roles of nonadditive gene expression, small RNAs, and epigenetic regulation, including circadian-mediated metabolic pathways, in hybrid vigor and incompatibility, which could lead to better use and exploitation of the increased biomass and yield in hybrids and allopolyploids for food, feed, and biofuels.
The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2−/−-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2−/−-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-β-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2−/−-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2−/−-Tgmice. The reduced osteophyte formation in Hspg2−/−-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-β model, the osteophyte size and maturation were also significantly reduced in Hspg2−/−-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy.
Synovial perlecan; Osteophyte; Osteoarthritis; TGF-β Synovium
To assess relationships of acetabular volume (AV), femoral head volume (FV), and portion of the femoral head within in the acetabulum (FVIA) with each other and with degrees of hip joint laxity and degenerative joint disease from youth to maturity in dogs predisposed to developing hip joint osteoarthritis (OA).
46 mixed-breed half- or full-sibling hound-type dogs.
The distraction index (DI), AV, FV, FVIA, and degree of osteoarthritis (OA score) were quantified in 1 hip joint at 16, 32, and 104 weeks of age. Relationships among variables were evaluated within and between ages. Ratios corresponding to OA scores were compared within ages. Differences among 16-week ratios corresponding to 32-week OA scores and among 16- and 32-week ratios corresponding to 104-week OA scores were evaluated.
Significant positive relationships existed between FV and AV across ages as well as between FVIA/FV and FVIA/AV and between DI and OA score across and within most ages. Such relationships also existed within these variables across most ages. Negative relationships of DI and OA scores with FVIA/FV and FVIA/AV within and among all ages were significant. Sixteen-week AVs, FVs, and FVIAs were greater and FV/AVs and OA scores were less than 32- and 104-week values. The 32-week FVIA/FV was less than 16- and 104-week values, and the 32-week FVIA/AV was less than the 104-week value. The FVIA/FV and FVIA/AV were lower and the DI was higher with higher OA scores within and among most ages.
Conclusions and Clinical Relevance
Structural volumes in lax canine hip joints changed predictably relative to each other during growth, despite degenerative changes. Measures developed in this study may augment current diagnosis and treatment strategies for hip dysplasia in dogs.
Objective: To determine whether the magnitude of the genetic influence on the development of hip osteoarthritis (OA) varies according to the radiographic phenotype within families.
Participants and methods: 331 families in which at least one sibling (index participant) had undergone total hip replacement for OA and whose preoperative x ray findings were available; 505 siblings of these index participants, who have high exposure to genetic risk of hip OA; and 1718 participants who had previously undergone intravenous urography, representative of the average general population exposure to genetic risk. Prevalence of hip OA was determined by individual radiographic features and minimum hip joint space. OA phenotype was partitioned according to pattern of femoral head migration and osteophyte bone response. Age adjusted odds ratios for hip OA in siblings, stratified according to phenotypic pattern in their index sibling, were assessed by unconditional logistic regression.
Results: The superior pattern of femoral head migration was more common in men, and the axial pattern more common in women. A poor bone response (absent osteophytosis) was associated with an indeterminate pattern of migration. The age adjusted odds ratios for definite hip OA were twofold higher in siblings of index participants who had no osteophyte response than in siblings whose index case had any degree of osteophyte (OR 2.05, 95% CI 1.12 to 3.76). The risk of the siblings from these families having undergone hip replacement themselves was threefold higher. Patterns of migration and bone response were not concordant within families, even among same sex siblings.
Conclusion: Careful phenotypic characterisation is essential for genetic studies of hip OA. The results of these studies are likely to be influenced by the phenotypic pattern of hip disease, particularly osteophyte bone response.
The association between progression of knee osteoarthritis and progression of osteoarthritis at sites distant from the knee is unclear because of a lack of multisite longitudinal progression data.
To examine the association between radiological progression of knee osteoarthritis and osteoarthritis of the hands, hips, and lumbar spine in a population based cohort.
914 women had knee x rays taken 10 years apart, which were read for the presence of osteophytes and joint space narrowing (JSN). Progression status was available for hand, hip, and lumbar spine x rays over the same 8 to 10 year period. The association between progression of knee osteoarthritis and osteoarthritis at other sites was analysed using odds ratios (OR) and 95% confidence intervals (CI) in logistic regression models.
89 of 133 women had progression of knee osteoarthritis based on osteophytes, and 51 of 148 based on JSN definition. Progression of JSN in the knee was predicted by progression in lumbar spine disc space narrowing (OR = 2.9 (95% CI 1.2 to 7.5)) and hip JSN (OR = 2.0 (1.0 to 4.2)). No consistent effects were seen for hand osteoarthritis. The associations remained after adjustment for age and body mass index.
Progression of knee osteoarthritis is associated with progression of lumbar spine and hip osteoarthritis. This may have implications for trial methodology, the selection of patients for osteoarthritis research, and advice for patients on prognosis of osteoarthritis.
osteoarthritis; knee; lumbar spine; outcome
Bone is a fundamental component of the disordered joint homeostasis seen in osteoarthritis, a disease that has been primarily characterized by the breakdown of articular cartilage accompanied by local bone changes and a limited degree of joint inflammation. In this review we consider the role of computed tomography imaging and computational analysis in osteoarthritis research, focusing on subchondral bone and osteophytes in the hip. We relate what is already known in this area to what could be explored through this approach in the future in relation to both clinical research trials and the underlying cellular and molecular science of osteoarthritis. We also consider how this area of research could impact on our understanding of the genetics of osteoarthritis.
bone; hip; osteoarthritis; subchondral; osteophyte; morphology; histology; genetics
The primary feature of osteoarthritis is cartilage loss. In addition, osteophytes can frequently be observed. Transforming growth factor‐β (TGFβ) has been suggested to be associated with protection against cartilage damage and new cartilage formation as seen in osteophytes.
To study TGFβ and TGFβ signalling in experimental osteoarthritis to gain insight into the role of TGFβ in cartilage degradation and osteophyte formation during osteoarthritis progression.
Histological sections of murine knee joints were stained immunohistochemically for TGFβ3 and phosphorylated SMAD‐2 (SMAD‐2P). Expression patterns were studied in two murine osteoarthritis models, representing spontaneous (STR/ort model) and instability‐associated osteoarthritis (collagenase‐induced instability model).
TGFβ3 and SMAD‐2P staining was increasingly reduced in cartilage during osteoarthritis progression in both models. Severely damaged cartilage was negative for TGFβ3. In contrast, bone morphogenetic protein‐2 (BMP‐2) expression was increased. In chondrocyte clusters, preceding osteophyte formation, TGFβ3 and SMAD‐2P were strongly expressed. In early osteophytes, TGFβ3 was found in the outer fibrous layer, in the peripheral chondroblasts and in the core. Late osteophytes expressed TGFβ3 only in the fibrous layer. SMAD‐2P was found throughout the osteophyte at all stages. In the late‐stage osteophytes, BMP‐2 was strongly expressed.
Data show that lack of TGFβ3 is associated with cartilage damage, suggesting loss of the protective effect of TGFβ3 during osteoarthritis progression. Additionally, our results indicate that TGFβ3 is involved in early osteophyte development, whereas BMP might be involved in late osteophyte development.
Biomechanic factors play a role in the pathogenesis of knee osteoarthritis. The aim of the study was to find out whether there is a relation between femoral, acetabular anteversions, anterior, posterior acetabular coverages and primary osteoarthritis of the knee.
Thirty patients with primary osteoarthritis of the knee and 29 control subjects were enrolled into the study. Femoral anteversion, acetabular anteversion, McKibbin’s instability index, anterior acetabular sector and posterior acetabular sector angles were measured using tomographic scanograms.
There was no difference between groups for each parameter (P > 0.05).
This study did not show any relationship between the axial plane changes in the hip joint and primary knee osteoarthritis.
Osteoarthritis; Knee; Anteversion
The recent discovery of a lineage of gray wolf in North-East Africa suggests the presence of a cryptic canid on the continent, the African wolf Canis lupus lupaster. We analyzed the mtDNA diversity (cytochrome b and control region) of a series of African Canis including wolf-like animals from North and West Africa. Our objectives were to assess the actual range of C. l. lupaster, to further estimate the genetic characteristics and demographic history of its lineage, and to question its taxonomic delineation from the golden jackal C. aureus, with which it has been considered synonymous. We confirmed the existence of four distinct lineages within the gray wolf, including C. lupus/familiaris (Holarctic wolves and dogs), C. l. pallipes, C. l. chanco and C. l. lupaster. Taxonomic assignment procedures identified wolf-like individuals from Algeria, Mali and Senegal, as belonging to C. l. lupaster, expanding its known distribution c. 6,000 km to the west. We estimated that the African wolf lineage (i) had the highest level of genetic diversity within C. lupus, (ii) coalesced during the Late Pleistocene, contemporaneously with Holarctic wolves and dogs, and (iii) had an effective population size of c. 80,000 females. Our results suggest that the African wolf is a relatively ancient gray wolf lineage with a fairly large, past effective population size, as also suggested by the Pleistocene fossil record. Unique field observations in Senegal allowed us to provide a morphological and behavioral diagnosis of the African wolf that clearly distinguished it from the sympatric golden jackal. However, the detection of C. l. lupaster mtDNA haplotypes in C. aureus from Senegal brings the delineation between the African wolf and the golden jackal into question. In terms of conservation, it appears urgent to further characterize the status of the African wolf with regard to the African golden jackal.
The study aims to determine the role of domestic dogs in transmission of visceral leishmaniasis in eastern Sudan. A cross-sectional survey was conducted in 10 villages along the River Rahad in eastern Sudan to elucidate the role of domestic dogs (Canis familiaris, Linnaeus, 1758) as a reservoir host of Leishmania donovani. In this study, 87 dogs were screened for infection by Leishmania donovani. Blood and lymph node samples were taken from 87 and 33 dogs respectively and subsequently screened by the Polymerase Chain Reaction (PCR) and Direct Agglutination Test (DAT) test. Additional lymph node smears were processed for microscopy and parasite culture. Host preference of the visceral leishmaniasis (VL) vector in the area, Phlebotomus orientalis, and other sandflies for the Nile rat (Arvicanthis niloticus, É. Geoffrey, 1803), the genet (Genetta genetta, Linnaeus, 1758), the mongoose (Herpeistes ichneumon, Linnaeus, 1758), and the domestic dog were determined by counting numbers of sand flies attracted to CDC traps that were baited by these animals.
DAT on blood samples detected anti-Leishmania antibodies in 6 samples (6.9%). Two out of 87 (2.3%) blood samples tested were PCR positive, giving an amplification product of 560 bp. The two positive samples by PCR were also positive by DAT. However, none of the 33 lymph nodes aspirates were Leishmania positive when screened by microscopy, culture and genus-specific PCR. The dog-baited trap significantly attracted the highest number of P. orientalis and sand fly species (P < 0.001). This was followed by the Egyptian mongoose baited trap and less frequently by the genet baited trap.
It is concluded that the results obtained from host attraction studies indicate that dog is more attractive for P. orientalis than Egyptian mongoose, common genet and Nile rat.
The relation between acetabular dysplasia and osteoarthritis of the hip was examined in a series of 1516 pelvic radiographs taken for non-skeletal indications. Osteoarthritis was assessed by measuring joint space, and dysplasia by the centre-edge angle and acetabular depth. In contrast with previous studies of patients with symptomatic osteoarthritis of the hip, no evidence that dysplasia predisposes to osteoarthritis was found. Possible reasons for the discrepancy are discussed. It was concluded that although acetabular dysplasia may lead to osteoarthritis of the hip in some subjects, it is unlikely to be an important cause of the disease in men.
The osteoarthritic diseases are common disorders characterized by progressive destruction of the articular cartilage in the joints, and associated with remodeling of the subchondral bone, synovitis and the formation of bone outgrowths at the joint margins, osteophytes. From the clinical perspective, osteoarthritis leads to joint pain and loss of function. Osteoarthritis is the leading cause of progressive disability. New data from genetic, translational and basic research have demonstrated that pathways with essential roles in joint and bone development also contribute to the postnatal homeostasis of the articular cartilage and are involved in osteoarthritis, making these potential therapeutic targets. Other systems of interest are the tissue-destructive enzymes that break down the extracellular matrix of the cartilage as well as mediators of inflammation that contribute to synovitis. However, the perspective of a durable treatment over years to decades highlights the need for a personalized medicine approach encompassing a global view on the disease and its management, thereby including nonpharmaceutical approaches such as physiotherapy and advanced surgical methods. Integration of novel strategies based on their efficacy and safety with the identification of individuals at risk and optimal individual rehabilitation management remains a major challenge for the medical community in particular, as the incidence of osteoarthritis is likely to further increase with the overall aging of the population.
High-quality sequencing of the dog (Canis lupus familiaris) genome has enabled enormous progress in genetic mapping of canine phenotypic variation. The red fox (Vulpes vulpes), another canid species, also exhibits a wide range of variation in coat color, morphology, and behavior. Although the fox genome has not yet been sequenced, canine genomic resources have been used to construct a meiotic linkage map of the red fox genome and begin genetic mapping in foxes. However, a more detailed gene-specific comparative map between the dog and fox genomes is required to establish gene order within homologous regions of dog and fox chromosomes and to refine breakpoints between homologous chromosomes of the 2 species. In the current study, we tested whether canine-derived gene–containing bacterial artificial chromosome (BAC) clones can be routinely used to build a gene-specific map of the red fox genome. Forty canine BAC clones were mapped to the red fox genome by fluorescence in situ hybridization (FISH). Each clone was uniquely assigned to a single fox chromosome, and the locations of 38 clones agreed with cytogenetic predictions. These results clearly demonstrate the utility of FISH mapping for construction of a whole-genome gene-specific map of the red fox. The further possibility of using canine BAC clones to map genes in the American mink (Mustela vison) genome was also explored. Much lower success was obtained for this more distantly related farm-bred species, although a few BAC clones were mapped to the predicted chromosomal locations.
Canis lupus familiaris; comparative genomics; FISH; Mustela vison; Vulpes vulpes
Structural variation contributes to the rich genetic and phenotypic diversity of the modern domestic dog, Canis lupus familiaris, although compared to other organisms, catalogs of canine copy number variants (CNVs) are poorly defined. To this end, we developed a customized high-density tiling array across the canine genome and used it to discover CNVs in nine genetically diverse dogs and a gray wolf.
In total, we identified 403 CNVs that overlap 401 genes, which are enriched for defense/immunity, oxidoreductase, protease, receptor, signaling molecule and transporter genes. Furthermore, we performed detailed comparisons between CNVs located within versus outside of segmental duplications (SDs) and find that CNVs in SDs are enriched for gene content and complexity. Finally, we compiled all known dog CNV regions and genotyped them with a custom aCGH chip in 61 dogs from 12 diverse breeds. These data allowed us to perform the first population genetics analysis of canine structural variation and identify CNVs that potentially contribute to breed specific traits.
Our comprehensive analysis of canine CNVs will be an important resource in genetically dissecting canine phenotypic and behavioral variation.
Osteoarthritis (OA) is a debilitating, progressive joint disease.
Similar to the disease progression in humans, sequential events of early cartilage degradation, subchondral osteopenia followed by sclerosis, and late osteophyte formation were demonstrated in the anterior cruciate ligament transection (ACLT) or ACLT with partial medial meniscectomy (ACLT + MMx) rat OA models. We describe a reliable and consistent method to examine the time dependent changes in the gene expression profiles in articular cartilage and subchondral bone.
Local regulation of matrix degradation markers was demonstrated by a significant increase in mRNA levels of aggrecanase-1 and MMP-13 as early as the first week post-surgery, and expression remained elevated throughout the 10 week study. Immunohistochemistry confirmed MMP-13 expression in differentiated chondrocytes and synovial fibroblasts at week-2 and cells within osteophytes at week-10 in the surgically-modified-joints. Concomitant increases in chondrocyte differentiation markers, Col IIA and Sox 9, and vascular invasion markers, VEGF and CD31, peaked around week-2 to -4, and returned to Sham levels at later time points in both models. Indeed, VEGF-positive cells were found in the deep articular chondrocytes adjacent to subchondral bone. Osteoclastic bone resorption markers, cathepsin K and TRAP, were also elevated at week-2. Confirming bone resorption is an early local event in OA progression, cathepsin K positive osteoclasts were found invading the articular cartilage from the subchondral region at week 2. This was followed by late disease events, including subchondral sclerosis and osteophyte formation, as demonstrated by the upregulation of the osteoanabolic markers runx2 and osterix, toward week-4 to 6 post-surgery.
In summary, this study demonstrated the temporal and cohesive gene expression changes in articular cartilage and subchondral bone using known markers of OA progression. The findings here support genome-wide profiling efforts to elucidate the sequential and complex regulation of the disease.
osteoarthritis; subchondral bone; cartilage degeneration; bone remodeling
Knowledge of infection reservoir dynamics is critical for effective disease control, but identifying reservoirs of multi-host pathogens is challenging. Here, we synthesize several lines of evidence to investigate rabies reservoirs in complex carnivore communities of the Serengeti ecological region in northwest Tanzania, where the disease has been confirmed in 12 carnivore species.Long-term monitoring data suggest that rabies persists in high-density domestic dog Canis familiaris populations (> 11 dogs km−2) and occurs less frequently in lower-density (< 5 dogs km−2) populations and only sporadically in wild carnivores.Genetic data show that a single rabies virus variant belonging to the group of southern Africa canid-associated viruses (Africa 1b) circulates among a range of species, with no evidence of species-specific virus–host associations.Within-species transmission was more frequently inferred from high-resolution epidemiological data than between-species transmission. Incidence patterns indicate that spill-over of rabies from domestic dog populations sometimes initiates short-lived chains of transmission in other carnivores.Synthesis and applications. The balance of evidence suggests that the reservoir of rabies in the Serengeti ecosystem is a complex multi-host community where domestic dogs are the only population essential for persistence, although other carnivores contribute to the reservoir as non-maintenance populations. Control programmes that target domestic dog populations should therefore have the greatest impact on reducing the risk of infection in all other species including humans, livestock and endangered wildlife populations, but transmission in other species may increase the level of vaccination coverage in domestic dog populations necessary to eliminate rabies.
carnivore; infectious disease; multi-host; phylogeny; rabies; reservoir; spill-over; transmission
Although many herbivores and omnivores have been shown to balance their intake of macronutrients when faced with nutritionally variable foods, study of this ability has been relatively neglected in carnivores, largely on the assumption that prey are less variable in nutrient composition than the foods of herbivores and omnivores and such mechanisms therefore unnecessary. We performed diet selection studies in 5 breeds of adult dog (Canis lupus familiaris) to determine whether these domesticated carnivores regulate macronutrient intake. Using nutritional geometry, we show that the macronutrient content of the diet was regulated to a protein:fat:carbohydrate ratio of approximately 30%:63%:7% by energy, a value that was remarkably similar across breeds. These values, which the analysis suggests are dietary target values, are based on intakes of dogs with prior experience of the respective experimental food combinations. On initial exposure to the diets (i.e., when naive), the same dogs self-selected a diet that was marginally but significantly lower in fat, suggesting that learning played a role in macronutrient regulation. In contrast with the tight regulation of macronutrient ratios, the total amount of food and energy eaten was far higher than expected based on calculated maintenance energy requirements. We interpret these results in relation to the evolutionary history of domestic dogs and compare them to equivalent studies on domestic cats.
Canis lupus; carnivore nutrition; domestication; domestic dog; geometric framework; macronutrient regulation; predation; right-angled mixture triangles
A radiological study of the sacroiliac joints was undertaken in 54 patients (32 males, 22 females) with vertebral ankylosing hyperostosis (VAH) and in 46 control patients (24 males, 22 females) matched for age and sex. The ages ranged from 38 to 90 years. The radiographs were taken in anteroposterior, oblique, and craniocaudal projections. The films were read for cranial, ventral, and caudal capsular ossifications, for ventral and caudal osteophytes, and for bone sclerosis. Cranial and/or ventral capsular ossifications were found in 28 (87.5%) males with VAH and in 4 (16.6%) control males (p less than 0.0005), but only in 2 females with VAH and no control female. Sacroiliac capsular ossifications in males with VaH are frequent from the onset, but complete bridging of the joint is not reached before the sixth decade. Women, either VAH or control, have more sacroiliac osteophytes than men. There were 11 out of 22 control women with osteophytes versus 4 out of 24 men (p less than 0.025). The incidence of osteophytes does not seem to increase with age after 50 years. Our findings support the idea of VAH being a distinct entity and not a major form of osteophytosis.
Objective: To evaluate whether familial aggregation of osteoarthritis differs by joint site in a sibling pair study (GARP) of patients with osteoarthritis at multiple sites.
Subjects: White Dutch probands aged 40 to 70 years and their siblings with primary osteoarthritis at multiple sites.
Methods: The diagnosis of knee, hip, and spine osteoarthritis was based on a combination of pain or stiffness on most days of the previous month and osteophytes or joint space narrowing on x ray. Hand osteoarthritis was defined by ACR criteria. Odds ratios (OR) were calculated for siblings and probands sharing disease in the same joints.
Results: 191 sibling pairs were included (85% women; mean age 60 years). In the probands, osteoarthritis was present in spine (76%), hands (77%), knees (37%), and hips (26%). The most common combinations in probands were spine–hand (59%), spine–knee (27%), and hand–knee (25%). The OR adjusted for age, sex, and body mass index for siblings to be affected in the same joint sites as the proband were increased in osteoarthritis of the hand (OR = 4.4 (95% confidence interval, 2.0 to 9.5)), hip (OR = 3.9 (1.8 to 8.4)), spine (OR = 2.2 (1.0 to 5.1)), hip–spine (OR = 4.7 (2.1 to 10.4)), and hand–hip (OR = 3.4 (1.1 to 10.4)). Siblings of probands with osteoarthritis in the knee did not have an increased likelihood of knee osteoarthritis.
Conclusions: In middle aged patients with familial osteoarthritis at multiple sites, familial aggregation of osteoarthritis was most striking for hand and hip but remarkably absent for the knee.