Martine Cohen-Solal

Inhibition of bone resorption blunts osteoarthritis in mice with high bone remodelling.

Background Osteoarthritis (OA) is characterised by cartilage degradation and bone lesions. Subchondral bone may be involved in the pathogenesis of cartilage matrix breakdown. Objective To assess the role of bone remodelling in OA by studying the effect of bisphosphonate on OA development in mice with high bone remodelling. Methods Mice overexpressing Runx2 (Runx2-Tg) under the control of collagen type I that displayed high bone remodelling were used. Joint instability was performed by partial medial meniscectomy to induce OA. Results Six weeks after surgery, tibial cartilage of Runx2-Tg mice displayed an increased number of ADAMTS-4- and ADAMTS-5-expressing chondrocytes compared with controls (p<0.05). This increase was higher in Runx2-Tg mice than in wild-type mice, although their OA score did not differ (2.5±0.6 vs 2.4±0.2, P=NS). Pamidronate reduced the OA score in Runx2-Tg mice but not in wild-type littermates (1.2±0.5 vs 2.7±0.4; p<0.05) despite the reduction of bone resorption and of the expression of cartilage proteases in both genotypes. Conclusions These findings support the hypothesis that the level of bone resorption influences cartilage metabolism and that inhibition might prevent the progression of OA. Targeting bone resorption might therefore provide an approach to the treatment of high bone resorbing forms of OA.

Dkk-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice.

Wnt signaling is a master regulator of joint homeostasis, but its role in osteoarthritis (OA) remains unclear. This study was undertaken to characterize the activation of Wnt/β‐catenin in knee joints of mice with OA and to assess how inhibiting this pathway in bone could affect cartilage.

Targeting Bone Alleviates Osteoarthritis in Osteopenic Mice and Modulates Cartilage Catabolism

Objective Subchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism. Methods OA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by real-time quantitative PCR. The role of osteoprotegerin (OPG) in the bone-cartilage crosstalk was tested using an OPG neutralizing antibody. Results Bone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p<0.05). In OP mice, E2 and PAM decreased ADAMTS-4 and -5 expression, while only PAM markedly reduced OA compared to PBS (2.0±0.63 vs 5.2±0.95; p<0.05). OPG/RANKL mRNA was increased in human bone explants treated with both drugs (2.2–3.7-fold). Moreover, supernatants from bone explants cultured with E2 or PAM reduced aggrecan cleavage and cartilage proteoglycan release (73±8.0% and 80±22% of control, respectively, p<0.05). This effect was reversed with osteoprotegerin blockade. Conclusion The inhibition of bone resorption by pamidronate in osteopenic mice alleviates the histological OA score with a reduction in the expression of aggrecanases. Bone soluble factors, such as osteoprotegerin, impact the cartilage response to catabolic factors. This study further highlights the importance of subchondral bone in the regulation of joint cartilage damage in OA.

Vertebral fractures are associated with increased cortical porosity in iliac crest bone biopsy of men with idiopathic osteoporosis.

In men, vertebral fractures are poorly associated with bone density, and both cortical and trabecular micro-architectural changes could contribute to bone fragility. Bone histomorphometry makes it possible to investigate both the thickness and porosity of cortical bone, which has been reported to have a major impact on the biomechanical properties of bone. We therefore conducted a cross sectional study using iliac crest biopsies to investigate the trabecular and cortical bone structure in men with or without vertebral fractures. We selected 93 bone biopsies from men with idiopathic osteoporosis (defined as a T-score <-2.5), between 40 and 70 years of age. Patients were divided into two groups on the basis of the presence (n=46) or absence (n=47) of prevalent vertebral fracture (VFX). We measured micro-architectural indices in trabecular and cortical bone by histomorphometry at the iliac crest. Patients with VFX had lower trabecular bone volume (BV/TV: 12.4+/-3.8 versus 14.7+/-3.1 % (m+/-SD)), p<0.01), higher trabecular separation (Tb.Sp: 871+/-279 versus 719+/-151 microm, p<0.01), and higher marrow star volume (V*(m.space): 1.617+/-1.257 versus 0.945+/-0.466 mm(3), p<0.01). Cortical thickness (Ct.Th) was the same in patients with or without VFX, whereas cortical porosity (Ct.Po) was higher in patients with VFX (6.5+/-2.6 versus 5.0+/-2.0 %, p<0.01), because their Haversian canals had higher mean areas (8291+/-4135 versus 5438+/-2809 microm(2), p<0.001). There was no correlation between any trabecular and cortical micro-architectural parameters. Using a logistic regression model, we evaluated the VFX as a function of the V*(m.space) and Ct.Po, adjusted for age. The odds-ratio of having a VFX was 3.89 (95% CI 1.19-12.7, p=0.02) for the third tertile of V*(m.space) (adjusted on age and Ct.Po), and 4.07 (95% CI 1.25-13.3, p=0.02) for the third tertile of Ct.Po (adjusted on age and V*(m.space)). Our data show that both trabecular and cortical bone microarchitecture contribute independently to vertebral fractures in men with idiopathic osteoporosis. In contrast to data reported in women, in men it is cortical porosity, and not cortical width, that is associated with vertebral fractures. This suggests that the cortical deficit is different in men and in women with fragility fractures.

Subtrochanteric/femoral shaft Versus hip fractures: Incidences and identification of risk factors

Subtrochanteric and femoral shaft (ST/FS) fractures are now considered to be fragility fractures in osteoporotic patients. Although rare, there is growing evidence of the burden that they constitute. Little is known about the change over time in incidence of ST/FS fractures. We assessed the incidence of ST/FS fractures and the associated risk factors from 2002 to 2009 compared with those of hip fractures. Data were obtained from the French National Database, which includes all hospital discharge codes from acute care facilities. Hospitalizations for primary surgical management of neck/trochanteric (hip) and ST/FS fractures in patients aged above 50 years were selected and described for different age groups. Incidences per million populations were calculated using the estimated French population adjusted for each year, age, and gender. We studied the change for each fracture site. The comorbidity factors related to these fractures were assessed in 2009 using multivariate logistic regression. From 2002 to 2009, the adjusted incidence of hip fractures decreased continuously from 4368 to 3662 in women (p < 0.0001), and a mild increase from 1476 to 1384 in men (p < 0.0001) after an initial decrease. In contrast, the incidence of ST/FS increased significantly in both genders (from 353 to 395 in women, from 146 to 159 in men). In 2009, the incidence of ST/FS in the general population remained low, reaching the levels of 412 in women and 168 in men, but were 2966 and 1461 in women and men aged >89 years. The adjusted risk of having a ST/FS fracture was significantly higher in a context of obesity (odds ratio [OR]: 2.26; 1.95–2.61) and dementia (OR: 1.23; 1.16–1.30), but decreased with age (OR: 0.83; 0.79–0.88) and hypertension (OR: 0.90; 0.86–0.95). In conclusion, ST/FS fractures mainly affect elderly people and incidence increased significantly from 2002 to 2009. Obesity and dementia are the risk factors associated with these rare fractures, compared with regular hip fractures.

Usefulness of bone density measurement in fallers.

The objective of this systematic literature review is to discuss the latest French recommendation issued in 2012 that a fall within the past year should lead to bone mineral density (BMD) measurement using dual-energy X-ray absorptiometry (DXA). This recommendation rests on four facts. First, osteoporosis and fall risk are the two leading risk factors for nonvertebral fractures in postmenopausal women. Second, BMD measurement using DXA supplies significant information on the fracture risk independently from the fall risk. Thus, when a fall occurs, the fracture risk increases as BMD decreases. Third, osteoporosis drugs have been proven effective in preventing fractures only in populations with osteoporosis defined based on BMD criteria. Finally, the prevalence of osteoporosis is high in patients who fall and increases in the presence of markers for frailty (e.g., recurrent falls, sarcopenia [low muscle mass and strength], limited mobility, and weight loss), which are risk factors for both osteoporosis and falls. Nevertheless, life expectancy should be taken into account when assessing the appropriateness of DXA in fallers, as osteoporosis treatments require at least 12months to decrease the fracture risk. Another relevant factor is the availability of DXA, which may be limited due to geographic factors, patient dependency, or severe cognitive impairments, for instance. Studies are needed to better determine how the fall risk and frailty should be incorporated into the fracture risk evaluation based on BMD and the FRAX® tool.

Protective role of systemic furin in immune response–induced arthritis

OBJECTIVE Rheumatoid arthritis (RA) is an autoimmune joint disease associated with chronic inflammation of the synovium that causes profound damage of joints. Inflammation results in part from the influx of immune cells secreting inflammatory cytokines and the reduction in the number of Treg cells. We undertook this study to assess the effect of furin, a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of both proteinase maturation and immune cells, in an experimental model of RA. METHODS The effect of furin and its inhibitor α1-PDX was tested in mice with collagen-induced arthritis (CIA). Joints were processed for histology and protein expression. Levels of cytokines were measured in joint tissue, and Treg cell numbers were measured in spleens. RESULTS Furin expression and activity were high in the synovial pannus in RA patients and mice with CIA. Systemic administration of furin prevented increases in the arthritis score, joint destruction, and bone loss, in contrast to systemic administration of the furin inhibitor α1-PDX, which enhanced these parameters. By preventing the development of synovial pannus, furin reduced the expression of metalloproteinases in the joints. In contrast, α1-PDX enhanced synovial proliferation and the expression and activity of matrix metalloproteinases. Furthermore, furin reversed the local Th1/Th2 balance and restored the number of Treg cells in the spleen, indicating mediation by immune cells. CONCLUSION These findings show the protective role of exogenous furin against RA, mediated by an immune response. The data suggest the potential therapeutic use of furin or its derivatives in autoimmune diseases including RA.

Recommandations pour la prise en charge de la déminéralisation osseuse dans la mucoviscidose

A high prevalence of low bone mineralization is documented in adult patients with cystic fibrosis (CF). Osteopenia is present in as much as 85% of adult patients and osteoporosis in 13 to 57% of them. In children, studies are discordant probably because of different control database. Denutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity are well known risk factors for poor bone health. Puberty is a critical period and requires a careful follow-up for an optimal bone peak mass. This review is a consensus statement established by the national working group of the French Federation of CF Centers to develop practice guidelines for optimizing bone health in patients with CF. Recommendations for screening and for calcium, vitamin D and K supplementation are given. Further work is needed to define indications for treatment with biphosphonates and anabolic agents.

Chondrocalcinosis of Femoro-Tibial and Proximal Tibio-Fibular Joints in Cadaveric Specimens: A High-Resolution CT Imaging Study of the Calcification Distribution

Objectives To analyze calcium deposits by computed tomography (CT) in femoro-tibial compartments and proximal tibio-fibular joints; to assess the relationship with CT-assessed osteoarthritis (OA). Methods 68 (34 pairs) cadaveric knees (mean age of 84) were scanned at high resolution CT. Menisci and hyaline cartilage calcifications in the femoro-tibial and proximal tibio-fibular joints were analyzed. OA was CT-assessed by the Kellgren and Lawrence score. Gross appearance of OA was evaluated on 29 left knees after dissection and India ink staining of tibial plateaus. Results In femoro-tibial joints, meniscal calcifications (MC) and hyaline cartilage calcifications (HCC) were detected in 23(34%) and 14(21%) knees respectively. Calcifications mainly involved the three meniscal segments and were mainly observed in all thirds of the femoro-tibial compartments. In proximal tibio-fibular joints, HCC were detected in 19(28%) knees. The association HCC-MC in femoro-tibial joints and between calcifications in femoro-tibial and proximal tibio-fibular joints was strong (p<0.0001). Femoro-tibial and proximal tibio-fibular CT-assessed OA were respectively found in 23(34%) and 19(28%) knees. HCC were significantly associated with femoro-tibial OA (p = 0.04) while MC were not (p = 0.34). OA macroscopic evaluation showed a mean surface of cartilage lesions of 35% (range 0.13–0.55). No significant difference was demonstrated regarding the CT-detection of MC, HCC or CT-assessed OA. Conclusions This is the first study to report a strong association of chondrocalcinosis between femoro-tibial and tibio-fibular joints in addition to a strong association between MC and HCC in femoro-tibial compartments. No significant relationship between chondrocalcinosis and OA was demonstrated.

Adrenomedullin22–52 combats inflammation and prevents systemic bone loss in murine collagen-induced arthritis

OBJECTIVE Adrenomedullin(22-52) is a truncated peptide derived from adrenomedullin, a growth factor with antiapoptotic and immunoregulatory properties. It can act as an agonist or an antagonist depending on cell type. Its in vivo effects are unknown, but adrenomedullin(22-52) could possess immunomodulatory properties. This study was undertaken to evaluate the effect of adrenomedullin(22-52) in a mouse model of arthritis. METHODS DBA/1 mice with collagen-induced arthritis (CIA) were treated with 1.2 μg/gm adrenomedullin(22-52) , adrenomedullin, or saline at arthritis onset. Bone mineral density was measured at the beginning of the experiment and when mice were killed. Mouse joints were processed for histologic analysis and protein studies, and spleens were examined for Treg cell expression. Cytokine expression was studied in mouse joint tissue and serum. RESULTS In mice with CIA, adrenomedullin and adrenomedullin(22-52) reduced clinical and histologic arthritis scores and shifted the pattern of articular and systemic cytokine expression from Th1 to Th2, as compared to untreated mice with CIA (controls). Tumor necrosis factor α, interleukin-6 (IL-6), and IL-17A levels were significantly decreased in the joints of mice with CIA treated with adrenomedullin or adrenomedullin(22-52) as compared to controls, whereas IL-4 and IL-10 levels were increased. Adrenomedullin(22-52) was more effective than adrenomedullin in modulating cytokine content and enhanced Treg cell function without changing Treg cell expression compared to controls. Adrenomedullin receptor binding and transcriptional adrenomedullin receptor expression were markedly increased in joints from controls, whereas adrenomedullin receptor binding was considerably decreased in treated animals. Mice with CIA treated with adrenomedullin or adrenomedullin(22-52) had considerably fewer apoptotic chondrocytes and diminished cartilage degradation. Adrenomedullin(22-52) completely prevented systemic bone loss by preserving osteoblastic activity, but without changes in osteoclastic activity. CONCLUSION Our findings indicate that adrenomedullin(22-52) , which has no vasoactive or tumor-inducing effects, is a potent antiinflammatory and bone-protective agent in this arthritis model.