Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis.

OBJECTIVE: To test whether single-nucleotide polymorphisms (SNPs) of the FRZB gene are associated with hip shape, and to determine whether FRZB variant alleles affect the relationship between hip shape and radiographic osteoarthritis (OA) of the hip. METHODS: A nested case-control study of Caucasian women, age ≥65 years, from the Study of Osteoporotic Fractures cohort was performed. Cases (n = 451) were defined as subjects with radiographic evidence of incident hip OA during followup, while controls (n = 601) were subjects in whom no radiographic hip OA was identified at baseline or followup. Statistical shape modeling (SSM) of the digitized hip radiographs was performed to assess the shape of the proximal femur, using 10 independent modes of shape variation generated by principal components analysis. In addition, center-edge angle and acetabular depth were assessed as geometric measurements of acetabular shape. The association of the rs288326 and rs7775 FRZB variant alleles with hip shape was analyzed using linear regression. The effect of these alleles on the relationship between hip shape and radiographic hip OA was analyzed using a logistic regression model with or without inclusion of interaction terms. RESULTS: The rs288326 and rs7775 alleles were associated with the shape of the proximal femur (SSM mode 2). There was a significant interaction between the rs288326 SNP and proximal femur shape (SSM mode 2) in predicting radiographic hip OA (P for interaction = 0.022). Among subjects with the rs288326 variant allele, there was an increased likelihood of radiographic hip OA in association with increasing quartiles of proximal femur shape mode 2 (for the fourth quartile of mode 2, odds ratio 2.5, 95% confidence interval 1.15, 5.25; P for linear trend = 0.02). CONCLUSION: The rs288326 and rs7775 FRZB SNPs are associated with the shape of the proximal femur. The presence of the rs288326 SNP alters the relationship between proximal femur shape and incident radiographic hip OA. These findings suggest that FRZB may serve an important role in determining hip shape and may modify the relationship between hip shape and OA.

Role of bone architecture and anatomy in osteoarthritis.

When considering the pathogenesis of osteoarthritis (OA), it is important to review the contribution of bone in addition to the contribution of cartilage and synovium. Although bone clearly plays a role in determining the distribution of biomechanical forces across joints, which in turn plays a role in the initiation of OA, it has also more recently been appreciated that bone may contribute in a biological sense to the pathogenesis of OA. Far from being a static structure, bone is a dynamic tissue undergoing constant remodeling, and it is clear from a number of radiographic and biochemical studies that bone and cartilage degradation occurs hand in hand. Whether the initial instigating event in OA occurs in cartilage or bone is not known, but it is clear that bony changes occur very early in the pathogenesis of OA and often predate radiographic appearance of the disease. This review focuses on the structural variants of both hip and knee that have been associated with OA and the ultrastructural bone changes in these sites occurring in early OA pathogenesis. This article is part of a Special Issue entitled "Osteoarthritis".

Effects of inflammation on bone: an update.

PURPOSE OF REVIEW: To present an updated summary of the relationship between inflammation and localized and generalized bone loss in the rheumatic diseases. RECENT FINDINGS: In addition to the well established role of inflammatory cytokines in promoting enhanced osteoclast function and bone loss, recent work has discovered the cytokine milieu may also inhibit osteoblast function and bone repair. The WNT and bone morphogenetic protein pathways provide molecular links between inflammation and altered bone homeostasis in chronic inflammatory states. These pathways and others have been the targets of emerging therapies for the management of inflammatory bone loss. SUMMARY: Inflammation and bone loss are linked through a number of molecular pathways. Both of these processes need to be addressed when designing an effective treatment strategy for the rheumatic diseases.

Active shape modeling of the hip in the prediction of incident hip fracture.

The objective of this study was to evaluate right proximal femur shape as a risk factor for incident hip fracture using active shape modeling (ASM). A nested case-control study of white women 65 years of age and older enrolled in the Study of Osteoporotic Fractures (SOF) was performed. Subjects (n = 168) were randomly selected from study participants who experienced hip fracture during the follow-up period (mean 8.3 years). Controls (n = 231) had no fracture during follow-up. Subjects with baseline radiographic hip osteoarthritis were excluded. ASM of digitized right hip radiographs generated 10 independent modes of variation in proximal femur shape that together accounted for 95% of the variance in proximal femur shape. The association of ASM modes with incident hip fracture was analyzed by logistic regression. Together, the 10 ASM modes demonstrated good discrimination of incident hip fracture. In models controlling for age and body mass index (BMI), the area under receiver operating characteristic (AUROC) curve for hip shape was 0.813, 95% confidence interval (CI) 0.771-0.854 compared with models containing femoral neck bone mineral density (AUROC = 0.675, 95% CI 0.620-0.730), intertrochanteric bone mineral density (AUROC = 0.645, 95% CI 0.589-0.701), femoral neck length (AUROC = 0.631, 95% CI 0.573-0.690), or femoral neck width (AUROC = 0.633, 95% CI 0.574-0.691). The accuracy of fracture discrimination was improved by combining ASM modes with femoral neck bone mineral density (AUROC = 0.835, 95% CI 0.795-0.875) or with intertrochanteric bone mineral density (AUROC = 0.834, 95% CI 0.794-0.875). Hips with positive standard deviations of ASM mode 4 had the highest risk of incident hip fracture (odds ratio = 2.48, 95% CI 1.68-3.31, p < .001). We conclude that variations in the relative size of the femoral head and neck are important determinants of incident hip fracture. The addition of hip shape to fracture-prediction tools may improve the risk assessment for osteoporotic hip fractures.

Assessment of bone remodelling in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To identify predictors of bone remodelling in children and young adults with SLE. METHODS: Ninety subjects with SLE aged 8-22 years underwent yearly measurements of height, bone age, bone turnover markers, serum Type I IFNs, SLEDAI and BMD. Predictors of bone turnover were examined using serum osteocalcin as a marker of bone formation and both serum tartrate-resistant acid phosphatase (TRAP) and urine N-telopeptide (NTx) as markers of bone resorption. RESULTS: Subjects demonstrated short stature, high BMI and bone age delay. A spine BMD Z-score of less than -2.0 was seen in 16.1% of subject visits. Serum osteocalcin was negatively correlated with glucocorticoid dose (Spearman rank correlation coefficient R = -0.34, P < 0.0001) but was not associated with SLEDAI after adjustment for confounders. Serum TRAP was negatively associated with SLEDAI, even after controlling for confounders (P = 0.04). Similar results were obtained for urine NTx. There was a negative association between TRAP and serum IFN-ß (P = 0.03). CONCLUSIONS: In this population of children and young adults with moderate lupus disease activity, glucocorticoid dose was a negative predictor of bone formation, whereas lupus disease activity was not. Interestingly, lupus disease activity was a negative predictor of bone resorption, suggesting that lupus disease activity is not the primary factor contributing to the bone deficits of childhood-onset SLE. The potential protective role of IFN-ß and the effects of SLE treatment on bone loss require further study.

Relationship between joint shape and the development of osteoarthritis.

PURPOSE OF REVIEW: To present an updated summary of the relationship between joint shape and the development of osteoarthritis, with a particular focus on osteoarthritis of the hip. RECENT FINDINGS: Osteoarthritis of the hip is highly heritable, with a genetic contribution estimated at 60%. Among the genes that have been linked to this disease are several that are involved in the development and maintenance of joint shape, including members of the Wingless (Wnt) and the bone morphogenetic protein (BMP) family. Several features of hip joint architecture, such as acetabular dysplasia, pistol grip deformity, wide femoral neck, altered femoral neck-shaft angle, appear to play an important role in the pathogenesis of osteoarthritis and may predate the development of osteoarthritis by decades. SUMMARY: Gene-environment interactions play a crucial role in the development of osteoarthritis. The architecture of joint shape is determined by a complex sequence spanning embryonic, childhood, and adult life and contributes to the pathogenesis of osteoarthritis.

Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4+ T cell Th1 cytokine production in vivo.

Glucose-regulated protein 94 (GRP94/gp96), the endoplasmic reticulum heat shock protein 90 paralog, elicits both innate and adaptive immune responses. Regarding the former, GRP94/gp96 stimulates APC cytokine expression and dendritic cell maturation. The adaptive component of GRP94/gp96 function reflects a proposed peptide-binding activity and, consequently, a role for native GRP94/gp96-peptide complexes in cross-presentation. It is by this mechanism that tumor-derived GRP94/gp96 is thought to suppress tumor growth and metastasis. Recent data have demonstrated that GRP94/gp96-elicited innate immune responses can be sufficient to suppress tumor growth and metastasis. However, the immunological processes activated in response to tumor Ag-negative sources of GRP94/gp96 are currently unknown. We have examined the in vivo immunological response to nontumor sources of GRP94/gp96 and report that administration of syngeneic GRP94/gp96- or GRP94/gp96-N-terminal domain-secreting KBALB fibroblasts to BALB/c mice stimulates CD11b(+) and CD11c(+) APC function and promotes bystander activation of CD4(+) T cell Th1 cytokine production. Only modest activation of CD8(+) T cell or NK cell cytolytic function was observed. The GRP94/gp96-dependent induction of CD4(+) T cell cytokine production was markedly inhibited by carrageenan, indicating an essential role for APC in this response. These results identify the bystander activation of CD4(+) T lymphocytes as a previously unappreciated immunological consequence of GRP94/gp96 administration and demonstrate that GRP94/gp96-elicited alterations in the in vivo cytokine environment influence the development of CD4(+) T cell effector functions, independently of its proposed function as a peptide chaperone.

The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity.

Vaccination of mice with tumor-derived stress proteins, such as Hsp70 and gp96 (GRP94), can elicit antitumor immune responses, yielding a marked suppression of tumor growth and metastasis. The molecular basis for this response is proposed to reflect a peptide-binding function for these proteins. In this view, stress proteins bind the antigenic peptide repertoire of their parent cell, and when provided to the immune system, tumor-derived stress protein-peptide complexes are processed by antigen-presenting cells (APCs) to yield the subsequent activation of tumor-directed cytotoxic T lymphocyte activity. This model predicts that stress proteins, whose primary intracellular function concerns the proper folding and assembly of nascent polypeptides, intersect with the cellular pathways responsible for the generation, processing, or assembly (or all) of peptide antigens onto nascent major histocompatability class I molecules. Recent insights into the pathways for peptide generation now allow this hypothesis to be critically examined, which is the subject of this review.

GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression.

In chemical carcinogenesis models, GRP94 (gp96) elicits tumor-specific protective immunity. The tumor specificity of this response is thought to reflect immune responses to GRP94-bound peptide antigens, the cohort of which uniquely identifies the GRP94 tissue of origin. In this study, we examined the apparent tissue restriction of GRP94-elicited protective immunity in a 4T1 mammary carcinoma model. We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis. In addition, vaccination with irradiated cells secreting the GRP94 NH(2)-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression. Conditioned media from cultures of GRP94 or GRP94 NTD-secreting fibroblasts elicited the up-regulation of major histocompatibility complex class II and CD86 in dendritic cell cultures, consistent with a natural adjuvant function for GRP94 and the GRP94 NTD. Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses.