[Show abstract][Hide abstract] ABSTRACT: Periostin (a product of Postn gene) is a matricellular protein which is increased in periosteal osteoblasts and osteocytes upon mechanical stimulation. We previously reported that periostin-deficient mice (Postn(-/-)) have low bone mass and a diminished response to physical activity due to a lack of sclerostin (a product of Sost gene) inhibition by mechanical loading. Here we hypothesized that periostin could play a central role in the control of bone loss during unloading induced by hindlimb suspension (HU). In Postn(+/+) mice (wildtype littermate), HU significantly decreased femur BMD, as well as trabecular BV/TV and thickness (Tb.Th). Cortical bone volume and thickness at the femoral midshaft, also significantly decreased. These changes were explained by an inhibition of endocortical and periosteal bone formation activity and correlated with a decrease of Postn expression and a consecutive increase in Sost early after HU. Whereas trabecular bone loss in Postn-/- mice was comparable to Postn(+/+) mice, HU did not significantly alter cortical bone microstructure and strength in Postn-/- mice. Bone formation remained unchanged in these mice, as Sost did not increase in the absence of periostin. In contrast, changes in Dkk1, Rankl and Opg expression in response to HU were similar to Postn(+/+) mice, indicating that changes in periostin expression were quite specifically related to changes in Sost. In conclusion, HU inhibits periostin expression, which in turn plays an important role in cortical bone loss through an increase in Sost. These results further indicate that periostin is an essential mediator of cortical bone response to mechanical forces (loading and unloading).
Bone 02/2015; 71. DOI:10.1016/j.bone.2014.10.011 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes where the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPARß(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPARß(-/-) mice and investigate both the mechanism behind those changes with age as well as their response to exercise. Compared to their wildtype, PPARß(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation and increased resorption. In addition, mesenchymal cells from PPARß(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPARγ, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPARß(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPARß controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPARß deficiency leads to glucose intolerance, decreased muscle function and reduced bone strength. On a molecular level, PPARß appears to regulate myostatin and PPARγ expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances.
[Show abstract][Hide abstract] ABSTRACT: High protein (> median:Hprot) vs. moderate (< median:MProt) intake was shown to enhance the positive impact of high physical activity (HPA) on proximal femur BMC/aBMD/Area in healthy prepubertal boys. We tested the hypothesis that this synergistic effect would track and influence bone structure and strength until mid-adolescence. BMC/aBMD/Area was measured at femoral neck (FN) and total hip (TotHip) by DXA in 176 boys at 7.4 ± 0.4 and 15.2 ± 0.5 years (± SD). Distal tibia (DistTib) microstructure and strength were also assessed at 15.2 years by high?resolution peripheral computerized tomography (HR-pQCT) and micro-finite element analysis (μFEA). The positive impact of HProt vs. MProt on FN and TotHip BMC/aBMD/Area, recorded at 7.4 years remained unabated at 15.2 years. At this age, at DistTib, HProt-HPA vs. MProt-HPA was associated (p < 0.001) with larger cross-sectional area (CSA, mm2), trabecular number (Tb.N, mm-1) and lower trabecular separation (Tb.Sp, μm). The interaction between physical activity and protein intake was signi ficant for CSA (p = 0.012) and Tb.N (p = 0.043). Under MProt (38.0 ± 6.9 g.d-1), a difference in PA from 168 ± 40 to 303 ± 54 kcal.d-1was associated with greater stiffness (kN/mm) and failure load (N) of +0.16 and +0.14 Z-score, respectively. In contrast, under HProt (56.2 ± 9.5 g.d-1), a difference in PA of similar magnitude, from 167 ± 33 to 324 ± 80 kcal.d-1, was associated with a larger difference in stiffness and failure load of +0.50 and +0.57 Z-score, respectively. In conclusion, the positive influence of relatively HProt on the impact of HPA on proximal femur macrostructure tracks from prepuberty to mid-late puberty. At this stage, the impact of HProt on HPA is also associated with microstructural changes that should confer greater mechanical resistance to weight-bearing bones. These results underscore the importance of protein intake and exercise synergistic interaction in the early prevention of adult osteoporosis.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2014; 29(10). DOI:10.1002/jbmr.2247 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Odanacatib, a selective cathepsin K inhibitor, decreases bone resorption, whereas osteoclast number increases and bone formation is maintained, perhaps even increased on some cortical surfaces. In a phase 2 clinical trial, post-menopausal women receiving odanacatib presented a sustained reduction of bone resorption markers, whereas procollagen type 1 N-terminal propeptide returned to normal. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. Blosozumab and romosozumab are sclerostin neutralizing antibodies that exert potent anabolic effects on both trabecular and cortical compartments. A phase 2 clinical trial has reported areal bone mineral density gains at spine and hip that were greater with romosozumab compared with placebo, but also with teriparatide. It also showed that antagonizing sclerostin results in a transient stimulation of bone formation but progressive inhibition of bone resorption. Other new medical entities that are promising for the treatment of osteoporosis include abaloparatide, a parathyroid hormone-related analogue with improved bone formation–resorption ratio.
Best Practice & Research: Clinical Endocrinology & Metabolism 08/2014; 28(6). DOI:10.1016/j.beem.2014.08.002 · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is complicated by the occurrence of fragility fractures. Over past years, various treatment options have become available, mostly potent antiresorptive agents such as bisphosphonates and denosumab. However, antiresorptive therapy cannot fully and rapidly restore bone mass and structure that has been lost because of increased remodelling. Alternatively recombinant human parathyroid hormone (rhPTH) analogues do increase the formation of new bone material. The bone formation stimulated by intermittent PTH analogues not only increases bone mineral density (BMD) and bone mass but also improves the microarchitecture of the skeleton, thereby reducing incidence of vertebral and nonvertebral fractures. Teriparatide, a recombinant human PTH fragment available in Switzerland, is reimbursed as second-line treatment in postmenopausal women and men with increased fracture risk, specifically in patients with incident fractures under antiresorptive therapy or patients with glucocorticoid-induced osteoporosis and intolerance to antiresorptives. This position paper focuses on practical aspects in the management of patients on teriparatide treatment. Potential first-line indications for osteoanabolic treatment as well as the benefits and limitations of sequential and combination therapy with antiresorptive drugs are discussed.
Swiss medical weekly: official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology 06/2014; 144:w13952. DOI:10.4414/smw.2014.13952 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Osteoporosis is a highly heritable trait. Among the genes associated with bone mineral density (BMD), the low-density lipoprotein receptor-related protein 5 gene (LRP5) has been consistently identified in Caucasians. However LRP5 contribution to osteoporosis in populations of other ethnicities remains poorly known.
To determine whether LRP5 polymorphisms Ala1330Val and Val667Met are associated with BMD in North Africans, these genotypes were analyzed in 566 post-menopausal Tunisian women with mean age of 59.5 ± 7.7 years, of which 59.1% have low bone mass (T-score < −1 at spine or hip).
In post-menopausal Tunisian women, 1330Val was weakly associated with reduced BMD T-score at lumbar spine (p = 0.047) but not femur neck. Moreover, the TT/TC genotypes tended to be more frequent in women with osteopenia and osteoporosis than in women with normal BMD (p = 0.066). Adjusting for body size and other potential confounders, LRP5 genotypes were no longer significantly associated with aBMD at any site.
The less common Val667Met polymorphism showed no association with osteoporosis. The Ala1330Val polymorphism is weakly associated with lower lumbar spine bone density and osteopenia/osteoporosis in postmenopausal Tunisian women. These observations expand our knowledge about the contribution of LRP5 genetic variation to osteoporosis risk in populations of diverse ethnic origin.
[Show abstract][Hide abstract] ABSTRACT: Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures. Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone to loading. Whether and how periostin influences damage and the injury response to fatigue remains unknown. We investigated the skeletal response of Postn-/- and Postn+/+ mice after fatigue stimulus by axial compression of their tibia. In Postn+/+ mice, cracks number and surface (CsNb, CsS) increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn+/+ mice. At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. In Postn-/- mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn+/+. Fatigue significantly increased CsNb and CsS in Postn-/-, but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either after fatigue in Postn-/- , and the level of damage remained high even after 30 days. As a result, strength remained compromised in Postn-/- mice. Contrary to Postn+/+ , which osteocytic lacunae showed a change in the degree of anisotropy (DA) after fatigue, Postn-/- showed no DA change. Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue. These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures.
PLoS ONE 10/2013; 8(10):e78347. DOI:10.1371/journal.pone.0078347 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bisphosphonates are the major treatment of choice for osteoporosis, given that they are attached preferentially by bone and significantly reduce the risk of fractures. Oral bisphosphonates are poorly absorbed (usually less than 1% for nitrogen-containing bisphosphonates) and when taken with food or beverages create complexes that cannot be absorbed. For this reason, they must be taken on an empty stomach, and a period of up to 2 hours must elapse before the consumption of any food or drink other than plain water. This routine is not only inconvenient but can lead to discontinuation of treatment, and when mistakenly taken with food, may result in misdiagnosis of resistance to or failure of treatment. The development of an enteric-coated delayed-release formulation of risedronate with the addition of the calcium chelator, ethylenediaminetetraacetic acid (EDTA), a widely used food stabilizer, eliminates the need for fasting without affecting the bioavailability of risedronate or its efficacy.
[Show abstract][Hide abstract] ABSTRACT: Context:Sclerostin inhibits bone formation and is involved in the bone response to mechanical loading, but the role and significance of circulating sclerostin is poorly understood.Objective:We assessed the association between serum sclerostin and calcitropic hormones, bone turnover marker levels, bone mineral content/density (BMC/BMD), and microstructure using three different immunoassays.Design, Setting, and Participants:In a cross-sectional study, serum sclerostin was measured in a cohort of 187 healthy subjects (98 women; 89 men) aged 65±1 (x±SD) years.Results:Overall, mean sclerostin (95% CI) was 37.3 (18.0-69.2) ng/l, 1165.8 (464.0-2296.4) ng/l, and 513.5 (250.7-950.9) ng/l with assays I, II and III, respectively. Serum sclerostin was higher in men with assays II and III. In all three assays, sclerostin and PTH were inversely correlated, only after adjustment for whole-body BMC (WB-BMC). After adjustment for sex and WB-BMC, the bone turnover markers P1NP and CTX negatively correlated, only with assay II. In all three assays, sclerostin positively correlated to WB-BMC, distal radius and distal tibia cortical area, cancellous bone volume (BV/TV) and trabecular number, and lumbar spine and proximal femur areal BMD following adjustment for sex.Conclusion:Sclerostin levels are markedly different according to the immunoassay used. Detection of an association with calcitropic hormones or turnover markers relies on the epitope recognized by the immunoassay and adjustment for bone mass.
The Journal of Clinical Endocrinology and Metabolism 07/2013; 98(9). DOI:10.1210/jc.2013-2113 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.
American Journal Of Pathology 04/2013; 182(6). DOI:10.1016/j.ajpath.2013.02.033 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis and periodontal disease (PD) are frequently associated in the elderly, both concurring to the loss of jaw alveolar bone and finally of teeth. Bisphosphonates improve alveolar bone loss but have also been associated with osteonecrosis of the jaw (ONJ), particularly using oncological doses of zoledronate. The effects and therapeutic margin of zoledronate on jaw bone therefore remain uncertain. We reappraised the efficacy and safety of Zoledronate (Zol) in ovariectomized (OVX) periostin (Postn)-deficient mice, a unique genetic model of systemic and jaw osteopenia. Compared to vehicle, Zol 1M (100 µg/kg/month) and Zol 1W (100 µg/kg/week) for 3 months both significantly improved femur BMD, trabecular bone volume on tissue volume (BV/TV) and cortical bone volume in both OVX Postn(+/+) and Postn(-/-) (all p<0.01). Zol 1M and Zol 1W also improved jaw alveolar and basal BV/TV, although the highest dose (Zol 1W) was less efficient, particularly in Postn(-/-). Zol decreased osteoclast number and bone formation indices, i.e. MAR, MPm/BPm and BFR, independently in Postn(-/-) and Postn(+/+), both in the long bones and in deep jaw alveolar bone, without differences between Zol doses. Zol 1M and Zol 1W did not reactivate inflammation nor increase fibrous tissue in the bone marrow of the jaw, whereas the distance between the root and the enamel of the incisor (DRI) remained high in Postn(-/-) vs Postn(+/+) confirming latent inflammation and lack of crestal alveolar bone. Zol 1W and Zol 1M decreased osteocyte numbers in Postn(-/-) and Postn(+/+) mandible, and Zol 1W increased the number of empty lacunae in Postn(-/-), however no areas of necrotic bone were observed. These results demonstrate that zoledronate improves jaw osteopenia and suggest that in Postn(-/-) mice, zoledronate is not sufficient to induce bone necrosis.
PLoS ONE 03/2013; 8(3):e58726. DOI:10.1371/journal.pone.0058726 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH. Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn(-/-) mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation.
Proceedings of the National Academy of Sciences 08/2012; 109(37):15048-53. DOI:10.1073/pnas.1203085109 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2-amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.
The Journal of clinical investigation 08/2012; 122(9):3295-306. DOI:10.1172/JCI63232 · 13.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As they age, mice deficient for the β2-adrenergic receptor (Adrb2(-/-) ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of β1-adrenergic receptor signaling and its interaction with β2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for β1-adrenergic receptors and/or β2-adrenergic receptors. Upon axial compression loading of the tibia, bone density, cancellous and cortical microarchitecture, as well as histomorphometric bone forming indices, were increased in both Adrb2(-/-) and wild-type (WT) mice, but not in Adrb1(-/-) nor in Adrb1b2(-/-) mice. Moreover, in the unstimulated femur and vertebra, bone mass and microarchitecture were increased in Adrb2(-/-) mice, whereas in Adrb1(-/-) and Adrb1b2(-/-) double knockout mice, femur bone mineral density (BMD), cancellous bone volume/total volume (BV/TV), cortical size, and cortical thickness were lower compared to WT. Bone histomorphometry and biochemical markers showed markedly decreased bone formation in Adrb1b2(-/-) mice during growth, which paralleled a significant decline in circulating insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3). Finally, administration of the β-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-κB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2(-/-) mice. Altogether, these results demonstrate that β1- and β2-adrenergic signaling exert opposite effects on bone, with β1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas β2-adrenergic receptor signaling mainly regulates bone resorption during aging.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2012; 27(6):1252-62. DOI:10.1002/jbmr.1594 · 6.83 Impact Factor