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1.
Curr Osteoporos Rep ; 21(4): 386-400, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37289382

RESUMO

PURPOSE OF REVIEW: This review summarizes recently published data and other developments around osteoanabolic osteoporosis therapies in patients with very high fracture risk, including those undergoing bone-related surgery. RECENT FINDINGS: Two osteoanabolic agents, abaloparatide and romosozumab, were recently approved for treatment of patients with osteoporosis at high fracture risk. These agents, along with teriparatide, are valuable for primary and secondary fracture prevention. Orthopedic surgeons are well positioned to facilitate secondary fracture prevention via referrals to fracture liaison services or other bone health specialist colleagues. This review aims to help surgeons understand how to identify patients with sufficiently high fracture risk to warrant consideration of osteoanabolic therapy. Recent evidence around the perioperative use and potential benefits of osteoanabolic agents in fracture healing and other orthopedic settings (e.g., spinal fusion and arthroplasty) in individuals with osteoporosis is also discussed. Osteoanabolic agents should be considered for patients with osteoporosis at very high fracture risk, including those with prior osteoporotic fractures and those with poor bone health who are undergoing bone-related surgery.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Fraturas por Osteoporose , Humanos , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Osteoporose/induzido quimicamente , Fraturas por Osteoporose/prevenção & controle , Teriparatida/uso terapêutico
2.
Int J Mol Sci ; 20(5)2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30813507

RESUMO

Immobilization of proteins has been examined to improve implant surfaces. In this study, titanium surfaces were modified with nanofunctionalized denosumab (cDMAB), a human monoclonal anti-RANKL IgG. Noncoding DNA oligonucleotides (ODN) served as linker molecules between titanium and DMAB. Binding and release experiments demonstrated a high binding capacity of cDMAB and continuous release. Human peripheral mononuclear blood cells (PBMCs) were cultured in the presence of RANKL/MCSF for 28 days and differentiated into osteoclasts. Adding soluble DMAB to the medium inhibited osteoclast differentiation. On nanofunctionalized titanium specimens, the osteoclast-specific TRAP5b protein was monitored and showed a significantly decreased amount on cDMAB-titanium in PBMCs + RANKL/MCSF. PBMCs on cDMAB-titanium also changed SEM cell morphology. In conclusion, the results indicate that cDMAB reduces osteoclast formation and has the potential to reduce osteoclastogenesis on titanium surfaces.


Assuntos
Denosumab/farmacologia , Monócitos/citologia , Monócitos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Titânio/farmacologia , Diferenciação Celular/efeitos dos fármacos , Humanos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Masculino , Monócitos/ultraestrutura , Nanopartículas/química , Ligante RANK/farmacologia , Solubilidade , Fosfatase Ácida Resistente a Tartarato/metabolismo
3.
Calcif Tissue Int ; 99(1): 99-109, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26945756

RESUMO

Bone fragility depends on bone mass, structure, and material properties, including damage. The relationship between bone turnover, fatigue damage, and the pattern and location of fractures, however, remains poorly understood. We examined these factors and their integrated effects on fracture strength and patterns in tibia. Adult male mice received RANKL (2 mg/kg/day), OPG-Fc (5 mg/kg 2×/week), or vehicle (Veh) 2 days prior to fatigue loading of one tibia by in vivo axial compression, with treatments continuing up to 28 more days. One day post fatigue, crack density was similarly increased in fatigued tibiae from all treatment groups. After 28 days, the RANKL group exhibited reduced bone mass and increased crack density, resulting in reduced bone strength, while the OPG-Fc group had greater bone mass and bone strength. Injury repair altered the pattern and location of fractures created by ex vivo destructive testing, with fractures occurring more proximally and obliquely relative to non-fatigued tibia. A similar pattern was observed in both non-fatigued and fatigued tibia of RANKL. In contrast, OPG-Fc prevented this fatigue-related shift in fracture pattern by maintaining fractures more distal and transverse. Correlation analysis showed that bone strength was predominantly determined by aBMD with minor contributions from structure and intrinsic strength as measured by nanoindentation and cracks density. In contrast, fracture location was predicted equally by aBMD, crack density and intrinsic modulus. The data suggest that not only bone strength but also the fracture pattern depends on previous damage and the effects of bone turnover on bone mass and structure. These observations may be relevant to further understand the mechanisms contributing to fracture pattern in long bone with different levels of bone remodeling, including atypical femur fracture.


Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Fraturas Ósseas/tratamento farmacológico , Tíbia/efeitos dos fármacos , Animais , Osso e Ossos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais , Tíbia/irrigação sanguínea
5.
FASEB J ; 26(3): 1110-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22125315

RESUMO

A unilateral injection of botulinum toxin A (BTxA) in the calf induces paralysis and profound loss of ipsalateral trabecular bone within days. However, the cellular mechanism underlying acute muscle paralysis-induced bone loss (MPIBL) is poorly understood. We hypothesized that MPIBL arises via rapid and extensive osteoclastogenesis. We performed a series of in vivo experiments to explore this thesis. First, we observed elevated levels of the proosteoclastogenic cytokine receptor activator for nuclear factor-κB ligand (RANKL) within the proximal tibia metaphysis at 7 d after muscle paralysis (+113%, P<0.02). Accordingly, osteoclast numbers were increased 122% compared with the contralateral limb at 5 d after paralysis (P=0.04) and MPIBL was completely blocked by treatment with human recombinant osteoprotegerin (hrOPG). Further, conditional deletion of nuclear factor of activated T-cells c1 (NFATc1), the master regulator of osteoclastogenesis, completely inhibited trabecular bone loss (-2.2±11.9%, P<0.01). All experiments included negative control assessments of contralateral limbs and/or within-animal pre- and postintervention imaging. In summary, transient muscle paralysis induced acute RANKL-mediated osteoclastogenesis resulting in profound local bone resorption. Elucidation of the pathways that initiate osteoclastogenesis after paralysis may identify novel targets to inhibit bone loss and prevent fractures.


Assuntos
Osso e Ossos/metabolismo , Músculo Esquelético/metabolismo , Osteoclastos/metabolismo , Paralisia/metabolismo , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/prevenção & controle , Toxinas Botulínicas Tipo A/toxicidade , Contagem de Células , Feminino , Deleção de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacologia , Paralisia/induzido quimicamente , Músculo Quadríceps/metabolismo , Músculo Quadríceps/patologia , Proteínas Recombinantes/farmacologia , Tíbia/metabolismo , Fatores de Tempo
6.
J Bone Miner Res ; 38(3): 403-413, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36533719

RESUMO

Prolonged use of antiresorptives such as the bisphosphonate alendronate (ALN) and the RANKL inhibitor denosumab (DMAb) are associated with rare cases of atypical femoral fracture (AFF). The etiology of AFF is unclear, but it has been hypothesized that potent osteoclast inhibitors may reduce bone fatigue resistance. The purpose of this study was to quantify the relationship between antiresorptive treatment and fatigue life (cycles to failure) in bone from ovariectomized cynomolgus monkeys. We analyzed humeral bone from 30 animals across five treatment groups. Animals were treated for 12 months with subcutaneous (sc) vehicle (VEH), sc DMAb (25 mg/kg/month), or intravenous (iv) ALN (50 µg/kg/month). Another group received 6 months VEH followed by 6 months DMAb (VEH-DMAb), and the final group received 6 months ALN followed by 6 months DMAb (ALN-DMAb). A total of 240 cortical beam samples were cyclically tested in four-point bending at 80, 100, 120, or 140 MPa peak stress. High-resolution imaging and density measurements were performed to evaluate bone microstructure and composition. Samples from the ALN (p = 0.014), ALN-DMAb (p = 0.008), and DMAb (p < 0.001) groups illustrated higher fatigue-life measurements than VEH. For example, at 140 MPa the VEH group demonstrated a median ± interquartile range (IQR) fatigue life of 1987 ± 10593 cycles, while animals in the ALN, ALN-DMAb, and DMAb groups survived 9850 ± 13648 (+395% versus VEH), 10493 ± 16796 (+428%), and 14495 ± 49299 (+629%) cycles, respectively. All antiresorptive treatment groups demonstrated lower porosity, smaller pore size, greater pore spacing, and lower number of canals versus VEH (p < 0.001). Antiresorptive treatment was also associated with greater apparent density, dry density, and ash density (p ≤ 0.03). We did not detect detrimental changes following antiresorptive treatments that would explain their association with AFF. In contrast, 12 months of treatment may have a protective effect against fatigue fractures. © 2022 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Conservadores da Densidade Óssea , Doenças Ósseas , Animais , Alendronato/farmacologia , Denosumab/farmacologia , Macaca fascicularis , Densidade Óssea , Osso e Ossos , Conservadores da Densidade Óssea/farmacologia
7.
J Bone Joint Surg Am ; 105(15): 1145-1155, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37159527

RESUMO

BACKGROUND: Fracture repair involves the reactivation of developmental signaling cascades, including Wnt signaling that stimulates bone formation and bone regeneration. Rodent data indicate that dual inhibition of the Wnt signaling antagonists sclerostin and Dickkopf-1 (DKK1) increases callus bone volume and strength while increasing bone mass systemically. METHODS: We evaluated the effects of 16 weeks of subcutaneously administered carrier solution (vehicle, VEH), anti-sclerostin antibody (Scl-Ab), anti-DKK1 antibody (DKK1-Ab), or Scl-Ab plus DKK1-Ab combination therapy (COMBO) on ulnar osteotomy healing in nonhuman primates (cynomolgus monkeys; 20 to 22 per group). RESULTS: Scl-Ab and COMBO therapy increased systemic markers of bone formation versus VEH, with COMBO leading to synergistic increases versus Scl-Ab or DKK1-Ab monotherapies. The COMBO and Scl-Ab groups showed reduced serum markers of bone resorption versus VEH. The COMBO and DKK1-Ab groups exhibited greater callus bone mineral density (BMD), torsional stiffness, and torsional rigidity versus VEH. Lumbar vertebrae from the Scl-Ab and COMBO groups showed greater BMD and bone formation rate versus VEH, and the femoral mid-diaphysis of the Scl-Ab and COMBO groups showed greater periosteal and endocortical bone formation rates versus VEH. CONCLUSIONS: DKK1-Ab increased BMD and strength at the ulnar osteotomy site, Scl-Ab increased bone formation and BMD at uninjured skeletal sites, and Scl-Ab plus DKK1-Ab combination therapy induced all of these effects, in some cases to a greater degree versus 1 or both monotherapies. These results in nonhuman primates suggest that DKK1 preferentially regulates bone healing while sclerostin preferentially regulates systemic bone mass. CLINICAL RELEVANCE: Combination therapy with antibodies against sclerostin and DKK1 may offer a promising therapeutic strategy for both fracture treatment and fracture prevention.


Assuntos
Consolidação da Fratura , Fraturas Ósseas , Animais , Anticorpos Monoclonais/uso terapêutico , Osso e Ossos , Densidade Óssea , Osteogênese/fisiologia , Primatas
8.
Endocr Rev ; 29(2): 155-92, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18057140

RESUMO

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.


Assuntos
Doenças Ósseas/fisiopatologia , Remodelação Óssea/fisiologia , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Animais , Humanos
9.
Calcif Tissue Int ; 90(4): 330-42, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22382900

RESUMO

Relapse after orthodontic tooth movement is a significant problem in orthodontics. The purpose of this study was to examine the efficacy of the osteoclast inhibitor osteoprotegerin-Fc (OPG-Fc) for inhibiting postorthodontic relapse. Rat maxillary molars were moved mesially and allowed to relapse for 24 days. Low-dose (1 mg/kg) or high-dose (5 mg/kg) OPG-Fc or saline was injected adjacent to the molars during relapse. Tooth movement, micro-CT, histologic bone quality, and serum OPG and TRAP-5b were measured. OPG-Fc injections significantly diminished postorthodontic relapse from 63% (0.78/1.20 mm) of total movement in vehicle control rats to 31% (0.31/1.00 mm) in low-dose and 24% (0.28/1.16 mm) in high-dose OPG-Fc groups 24 days after appliance removal. Normalization of bone and periodontal tissues occurred as early as 8 and 16 days in the high- and low-dose OPG-Fc-treated groups, respectively, while the vehicle-treated group showed only partial tissue recovery 24 days following tooth movement. After 24 days of relapse, there was complete recovery to pre-tooth-movement values for bone volume fraction (BVF) and tissue mineral density (TMD) in both the low- and high-dose OPG-Fc groups, while BVF recovered only partially and TMD did not recover in the vehicle control group. Greatly elevated serum OPG levels and reduced serum TRAP-5b levels in OPG-Fc-treated animals indicated systemic exposure to locally injected drug. The profound decrease in postorthodontic relapse by local OPG-Fc administration indicates that osteoclasts are critical to bone maturation following tooth movement and points to the potential pharmacologic use of OPG-Fc or other RANKL inhibitors for orthodontic retention.


Assuntos
Osteoprotegerina/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Mobilidade Dentária/tratamento farmacológico , Dente/efeitos dos fármacos , Animais , Masculino , Osteoprotegerina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Recidiva , Dente/fisiologia , Técnicas de Movimentação Dentária
10.
Bone ; 164: 116517, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35961611

RESUMO

Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (µCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n = 10), s.c. denosumab (DMAb; 25 mg/kg, n = 9), or i.v. alendronate (ALN; 50 µg/kg, n = 10). Two more groups received 6 months of VEH followed by 6 months of DMAb (VEH-DMAb; n = 7) or 6 months of ALN followed by 6 months of DMAb (ALN-DMAb; n = 9). After treatment, humeri were harvested and µCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, µCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via µCT; no effects on trabecular morphology were observed. FE estimated strength based on µCT was higher after 12-months DMAb (p = 0.020) and ALN-DMAb (p = 0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Alendronato/farmacologia , Alendronato/uso terapêutico , Animais , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/farmacologia , Denosumab/uso terapêutico , Epífises , Feminino , Humanos , Úmero/diagnóstico por imagem , Macaca fascicularis , Osteoporose Pós-Menopausa/tratamento farmacológico , Ovariectomia , Porosidade , Microtomografia por Raio-X
11.
J Biol Chem ; 285(36): 28164-73, 2010 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-20558734

RESUMO

PTH stimulates osteoblastic cells to form new bone and to produce osteoblast-osteoclast coupling factors such as RANKL. Whether osteoclasts or their activity are needed for PTH anabolism remains uncertain. We treated ovariectomized huRANKL knock-in mice with a human RANKL inhibitor denosumab (DMAb), alendronate (Aln), or vehicle for 4 weeks, followed by co-treatment with intermittent PTH for 4 weeks. Loss of bone mass and microarchitecture was prevented by Aln and further significantly improved by DMAb. PTH improved bone mass, microstructure, and strength, and was additive to Aln but not to DMAb. Aln inhibited biochemical and histomorphometrical indices of bone turnover,--i.e. osteocalcin and bone formation rate (BFR) on cancellous bone surfaces-, and Dmab inhibited them further. However Aln increased whereas Dmab suppressed osteoclast number and surfaces. PTH significantly increased osteocalcin and bone formation indices, in the absence or presence of either antiresorptive, although BFR remained lower in presence of Dmab. To further evaluate PTH effects in the complete absence of osteoclasts, high dose PTH was administered to RANK(-/-) mice. PTH increased osteocalcin similarly in RANK(-/-) and WT mice. It also increased BMD in RANK(-/-) mice, although less than in WT. These results further indicate that osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation. However the magnitude of PTH anabolic effects on the skeleton, in particular its additive effects with antiresorptives, depends on the extent of the remodeling space, as determined by the number and activity of osteoclasts on bone surfaces.


Assuntos
Alendronato/farmacologia , Anticorpos Monoclonais/farmacologia , Osso e Ossos/metabolismo , Técnicas de Introdução de Genes , Osteoclastos/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Ligante RANK/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/genética , Alendronato/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Denosumab , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Ovariectomia , Hormônio Paratireóideo/administração & dosagem , Ligante RANK/administração & dosagem , Receptor Ativador de Fator Nuclear kappa-B/antagonistas & inibidores , Receptor Ativador de Fator Nuclear kappa-B/deficiência , Receptor Ativador de Fator Nuclear kappa-B/metabolismo
12.
Am J Pathol ; 175(2): 473-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19590040

RESUMO

Osteoporosis and vascular calcification frequently coincide. A potential mediator of bone metabolism and vascular homeostasis is the triad cytokine system, which consists of receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin. Unopposed RANKL activity in osteoprotegerin-deficient mice resulted in osteoporosis and vascular calcification. We therefore analyzed the effects of RANKL inhibition by denosumab, a human monoclonal antibody against RANKL, on vascular calcium deposition following glucocorticoid exposure. Prednisolone pellets were implanted into human RANKL knock-in (huRANKL-KI) mice, which unlike wild-type mice are responsive to denosumab. No histomorphological abnormalities or differences in aortic wall thickness were detected between wild-type and huRANKL-KI mice, regardless of treatment with prednisolone, denosumab, or both. However, concurrent treatment with denosumab reduced aortic calcium deposition of prednisolone-treated huRANKL-KI mice by up to 50%, based on calcium measurement. Of note, aortic calcium deposition in huRANKL-KI mice was correlated negatively with bone mineral density at the lumbar spine (P = 0.04) and positively with urinary excretion of deoxypyridinoline, a marker of bone resorption (P = 0.01). In summary, RANKL inhibition by denosumab reduced vascular calcium deposition in glucocorticoid-induced osteoporosis in mice, which is further evidence for the link between the bone and vascular systems. Therefore, the prevention of bone loss by denosumab might also be associated with reduced vascular calcification in certain conditions.


Assuntos
Anticorpos Monoclonais/farmacologia , Aorta/metabolismo , Calcinose/metabolismo , Cálcio/metabolismo , Osteoporose/metabolismo , Ligante RANK/antagonistas & inibidores , Ligante RANK/farmacologia , Animais , Anticorpos Monoclonais Humanizados , Aorta/patologia , Calcinose/patologia , Denosumab , Técnicas de Introdução de Genes , Humanos , Camundongos , Camundongos Mutantes , Osteoporose/patologia , Ligante RANK/genética , Ligante RANK/metabolismo
13.
Sci Rep ; 10(1): 16217, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004873

RESUMO

Destruction of the alveolar bone in the jaws can occur due to periodontitis, trauma or following tumor resection. Common reconstructive therapy can include the use of bone grafts with limited predictability and efficacy. Romosozumab, approved by the FDA in 2019, is a humanized sclerostin-neutralizing antibody (Scl-Ab) indicated in postmenopausal women with osteoporosis at high risk for fracture. Preclinical models show that Scl-Ab administration preserves bone volume during periodontal disease, repairs bone defects surrounding dental implants, and reverses alveolar bone loss following extraction socket remodeling. To date, there are no studies evaluating Scl-Ab to repair osseous defects around teeth or to identify the efficacy of locally-delivered Scl-Ab for targeted drug delivery. In this investigation, the use of systemically-delivered versus low dose locally-delivered Scl-Ab via poly(lactic-co-glycolic) acid (PLGA) microspheres (MSs) was compared at experimentally-created alveolar bone defects in rats. Systemic Scl-Ab administration improved bone regeneration and tended to increase cementogenesis measured by histology and microcomputed tomography, while Scl-Ab delivered by MSs did not result in enhancements in bone or cemental repair compared to MSs alone or control. In conclusion, systemic administration of Scl-Ab promotes bone and cemental regeneration while local, low dose delivery did not heal periodontal osseous defects in this study.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Proteínas Morfogenéticas Ósseas/imunologia , Marcadores Genéticos/imunologia , Microesferas , Periodonto/citologia , Regeneração , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/patologia , Animais , Masculino , Periodonto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Microtomografia por Raio-X
14.
Circulation ; 117(3): 411-20, 2008 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-18172035

RESUMO

BACKGROUND: The role of osteoprotegerin in vascular disease is unclear. Recent observational studies show that serum osteoprotegerin levels are associated with the severity and progression of coronary artery disease, atherosclerosis, and vascular calcification in patients. However, genetic and treatment studies in mice suggest that osteoprotegerin may protect against vascular calcification. METHODS AND RESULTS: To test whether osteoprotegerin induces or prevents vascular disease, we treated atherogenic diet-fed ldlr(-/-) mice with recombinant osteoprotegerin (Fc-OPG) or vehicle for 5 months. Vehicle-treated mice developed significant, progressive atherosclerosis with increased plasma osteoprotegerin levels, consistent with observational studies, and approximately 15% of these atherosclerotic lesions developed calcified cartilage-like metaplasia. Treatment with Fc-OPG significantly reduced the calcified lesion area without affecting atherosclerotic lesion size or number, vascular cytokines, or plasma cholesterol levels. Treatment also significantly reduced tissue levels of aortic osteocalcin, a marker of mineralization. CONCLUSIONS: These data support a role for osteoprotegerin in the vasculature as an inhibitor of calcification and a marker, rather than a mediator, of atherosclerosis.


Assuntos
Aterosclerose/patologia , Calcinose/tratamento farmacológico , Osteoprotegerina/farmacologia , Doenças Vasculares/patologia , Animais , Aorta , Aterosclerose/etiologia , Endotélio Vascular/química , Camundongos , Camundongos Knockout , Osteoprotegerina/sangue , Ligante RANK/sangue , RNA Mensageiro/sangue , Receptores de LDL/deficiência , Proteínas Recombinantes , Doenças Vasculares/etiologia
15.
J Appl Physiol (1985) ; 106(2): 582-95, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19074574

RESUMO

Spaceflight results in a number of adaptations to skeletal muscle, including atrophy and shifts toward faster muscle fiber types. To identify changes in gene expression that may underlie these adaptations, we used both microarray expression analysis and real-time polymerase chain reaction to quantify shifts in mRNA levels in the gastrocnemius from mice flown on the 11-day, 19-h STS-108 shuttle flight and from normal gravity controls. Spaceflight data also were compared with the ground-based unloading model of hindlimb suspension, with one group of pure suspension and one of suspension followed by 3.5 h of reloading to mimic the time between landing and euthanization of the spaceflight mice. Analysis of microarray data revealed that 272 mRNAs were significantly altered by spaceflight, the majority of which displayed similar responses to hindlimb suspension, whereas reloading tended to counteract these responses. Several mRNAs altered by spaceflight were associated with muscle growth, including the phosphatidylinositol 3-kinase regulatory subunit p85alpha, insulin response substrate-1, the forkhead box O1 transcription factor, and MAFbx/atrogin1. Moreover, myostatin mRNA expression tended to increase, whereas mRNA levels of the myostatin inhibitor FSTL3 tended to decrease, in response to spaceflight. In addition, mRNA levels of the slow oxidative fiber-associated transcriptional coactivator peroxisome proliferator-associated receptor (PPAR)-gamma coactivator-1alpha and the transcription factor PPAR-alpha were significantly decreased in spaceflight gastrocnemius. Finally, spaceflight resulted in a significant decrease in levels of the microRNA miR-206. Together these data demonstrate that spaceflight induces significant changes in mRNA expression of genes associated with muscle growth and fiber type.


Assuntos
Regulação da Expressão Gênica , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Voo Espacial , Ausência de Peso , Adaptação Fisiológica/genética , Animais , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica/métodos , Elevação dos Membros Posteriores , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Miostatina/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/genética , Reação em Cadeia da Polimerase , Proteínas Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Serina-Treonina Quinases TOR , Fatores de Tempo
16.
Clin Exp Metastasis ; 25(2): 119-29, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18064531

RESUMO

Bone metastases cause severe skeletal morbidity including fractures and hypercalcemia. Tumor cells in bone induce activation of osteoclasts, which mediate bone resorption and release of growth factors from bone matrix, resulting in a "vicious cycle" of bone breakdown and tumor proliferation. Receptor activator of NF-kappaB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival, and is blocked by a soluble decoy receptor, osteoprotegerin (OPG). In human malignancies that metastasize to bone, dysregulation of the RANK/RANKL/OPG pathway can increase the RANKL:OPG ratio, a condition which favors excessive osteolysis. In a mouse model of bone metastasis, RANKL protein levels in MDA-MB-231 (MDA-231) tumor-bearing bones were significantly higher than tumor-free bones. The resulting tumor-induced osteoclastogenesis and osteolysis was dose-dependently inhibited by recombinant OPG-Fc treatment, supporting the essential role for RANKL in this process. Using bioluminescence imaging in a mouse model of metastasis, we monitored the anti-tumor efficacy of RANKL inhibition on MDA-231 human breast cancer cells in a temporal manner. Treatment with OPG-Fc in vivo inhibited growth of MDA-231 tumor cells in bony sites when given both as a preventative (dosed day 0) and as a therapeutic agent for established bone metastases (dosed day 7). One mechanism by which RANKL inhibition reduced tumor burden appears to be indirect through inhibition of the "vicious cycle" and involved an increase in tumor cell apoptosis, as measured by active caspase-3. Here, we demonstrate for the first time that OPG-Fc treatment of mice with established bone metastases resulted in an overall improvement in survival.


Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias da Mama/patologia , Osteoprotegerina/farmacologia , Ligante RANK/metabolismo , Animais , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Osso e Ossos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Osteoprotegerina/genética , Ligante RANK/antagonistas & inibidores , Ligante RANK/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Transplante Heterólogo
17.
Biomarkers ; 13(7): 692-712, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19096963

RESUMO

Rats with collagen-induced arthritis (CIA) were necropsied on 14 occasions from 4 days after induction to 27 days after disease onset to evaluate the kinetics of local (joint protein extracts) and systemic (serum) levels of inflammatory and pro-erosive factors. Systemic increases in alpha1 acid glycoprotein and KC/GRO together with systemic and local enrichment of interleukin (IL)-1beta, IL-6, CCL2, transforming growth factor (TGF)-beta and elevated IL-1alpha and IL-18 in joint extracts preceded the onset of clinical disease. Systemic upregulation of IL-1beta, IL-6, TGF-beta CCL2, RANKL and prostaglandin E(2) (PGE(2)) during acute and/or chronic CIA coincided with systemic leukocytosis and a CD4+ T-cell increase in blood and spleen. In contrast, progression of joint erosions during clinical CIA was associated with intra-articular increases in IL-1alpha/beta, IL-6, IL-18, CCL2, KC/GRO and RANKL, and a dramatic decline in osteoprotegerin (OPG). These data indicate that systemic and local events in inflammatory arthritis can be discrete processes, driven by multiple cellular and humoral mediators with distinct temporospatial profiles.


Assuntos
Artrite Experimental/patologia , Biomarcadores/análise , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Linfócitos T CD4-Positivos , Colágeno , Citocinas/análise , Progressão da Doença , Sistema Imunitário , Inflamação , Mediadores da Inflamação/análise , Cinética , Leucocitose , Ratos , Fatores de Tempo
18.
Bone ; 116: 162-170, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077758

RESUMO

Serum calcium (Ca) is maintained in a narrow range through regulation of Ca metabolism in the intestine, kidney, and bone. Calcium is incorporated and resorbed from bone during bone remodeling via cellular processes as well as by exchange. Both routes contribute to calcium homeostasis. To assess the magnitude of bone turnover contribution to calcium homeostasis we labeled bone with a Ca tracer and measured Ca release following stimulation or suppression of bone resorption. Young growing male rats (n = 162) were dosed with 45Ca to label skeletal Ca. After a one-month period to allow the label to incorporate into the skeleton, rats were treated with a bone resorption antagonist (OPG), a bone resorption agonist (RANKL), or vehicle control (PBS). Serum and urine 45Ca and total Ca, and serum TRACP5b (a bone resorption biomarker), were monitored for 45 days following treatment. Tracer data were analyzed by a compartmental model using WinSAAM to quantify dynamic changes in Ca metabolism and identify sites of change following treatment. In RANKL treated rats, both serum 45Ca and serum TRACP5b were increased by >70% due to a 25-fold increase in bone resorption. In OPG treated rats, both serum 45Ca and serum TRACP5b were suppressed by >70% due to a 75% decrease in bone resorption, a 3-fold increase in bone formation, and a 50% increase in absorption. Because TRACP5b and 45Ca responded similarly, we conclude that Ca release from bone into serum occurs mostly via osteoclast-mediated bone resorption. However, because serum Ca concentration did not change with altered resorption in response to either RANKL or OPG treatment, we also conclude that serum Ca concentration under normal dietary conditions in young growing male rats is maintained by processes in addition to cellular bone resorption.


Assuntos
Reabsorção Óssea/sangue , Cálcio/sangue , Crescimento e Desenvolvimento , Osteoprotegerina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Reabsorção Óssea/urina , Cálcio/urina , Masculino , Modelos Biológicos , Osteoprotegerina/administração & dosagem , Osteoprotegerina/farmacologia , Ligante RANK/administração & dosagem , Ligante RANK/farmacologia , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/metabolismo
19.
J Mol Med (Berl) ; 96(6): 559-573, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29736604

RESUMO

The RANK (receptor activator of nuclear factor κB)/RANKL (RANK ligand)/OPG (osteoprotegerin) axis is activated after myocardial infarction (MI), but its pathophysiological role is not well understood. Here, we investigated how global and cell compartment-selective inhibition of RANKL affects cardiac function and remodeling after MI in mice. Global RANKL inhibition was achieved by treatment of human RANKL knock-in (huRANKL-KI) mice with the monoclonal antibody AMG161. huRANKL-KI mice express a chimeric RANKL protein wherein part of the RANKL molecule is humanized. AMG161 inhibits human and chimeric but not murine RANKL. To dissect the pathophysiological role of RANKL derived from hematopoietic and mesenchymal cells, we selectively exchanged the hematopoietic cell compartment by lethal irradiation and across-genotype bone marrow transplantation between wild-type and huRANKL-KI mice, exploiting the specificity of AMG161. After permanent coronary artery ligation, mice were injected with AMG161 or an isotype control antibody over 4 weeks post-MI. MI increased RANKL expression mainly in cardiomyocytes and scar-infiltrating cells 4 weeks after MI. Only inhibition of RANKL derived from hematopoietic cellular sources, but not global or mesenchymal RANKL inhibition, improved post-infarct survival and cardiac function. Mechanistically, hematopoietic RANKL inhibition reduced expression of the pro-inflammatory cytokine IL-1ß in the cardiac cellular infiltrate. In conclusion, inhibition of RANKL derived from hematopoietic cellular sources is beneficial to maintain post-ischemic cardiac function by reduction of pro-inflammatory cytokine production. KEY MESSAGES: Experimental myocardial infarction (MI) augments cardiac RANKL expression in mice. RANKL expression is increased in cardiomyocytes and scar-infiltrating cells after MI. Global or mesenchymal cell RANKL inhibition has no influence on cardiac function after MI. Inhibition of RANKL derived from hematopoietic cells improves heart function post-MI. Hematopoietic RANKL inhibition reduces pro-inflammatory cytokines in scar-infiltrating cells.


Assuntos
Células-Tronco Hematopoéticas , Ligante RANK/antagonistas & inibidores , Animais , Citocinas , Masculino , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/terapia , Miócitos Cardíacos , Osteoprotegerina , Receptor Ativador de Fator Nuclear kappa-B , Traumatismo por Reperfusão
20.
J Bone Miner Res ; 22(10): 1534-47, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17576164

RESUMO

UNLABELLED: Skeletal anabolism with PTH is achieved through daily injections that result in brief exposure to the peptide. We hypothesized that similar anabolic effects could be achieved with less frequent but more sustained exposures to PTH. A PTH-Fc fusion protein with a longer half-life than PTH(1-34) increased cortical and cancellous BMD and bone strength with once- or twice-weekly injections. INTRODUCTION: The anabolic effects of PTH are currently achieved with, and thought to require, daily injections that result in brief exposure to the peptide. We hypothesized that less frequent but more sustained exposures to PTH could also be anabolic for bone, provided that serum levels of PTH were not constant. MATERIALS AND METHODS: PTH(1-34) was fused to the Fc fragment of human IgG1 to increase the half-life of PTH. Skeletal anabolism was examined in mice and rats treated once or twice per week with this PTH-Fc fusion protein. RESULTS: PTH-Fc and PTH(1-34) had similar effects on PTH/PTHrP receptor activation, internalization, and signaling in vitro. However, PTH-Fc had a 33-fold longer mean residence time in the circulation of rats compared with that of PTH(1-34). Subcutaneous injection of PTH-Fc once or twice per week resulted in significant increases in bone volume, density, and strength in osteopenic ovariectomized mice and rats. These anabolic effects occurred in association with hypercalcemia and were significantly greater than those achievable with high concentrations of daily PTH(1-34). PTH-Fc also significantly improved cortical bone volume and density under conditions where daily PTH(1-34) did not. Antiresorptive co-therapy with estrogen further enhanced the ability of PTH-Fc to increase bone mass and strength in ovariectomized rats. CONCLUSIONS: These results challenge the notion that brief daily exposure to PTH is essential for its anabolic effects on cortical and cancellous bone. PTH-derived molecules with a sustained circulating half-life may represent a powerful and previously undefined anabolic regimen for cortical and cancellous bone.


Assuntos
Anabolizantes/administração & dosagem , Anabolizantes/farmacologia , Osso e Ossos/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Hormônio Paratireóideo/administração & dosagem , Hormônio Paratireóideo/farmacologia , Proteínas Recombinantes/farmacologia , Envelhecimento/fisiologia , Anabolizantes/farmacocinética , Animais , Arrestinas/metabolismo , Osso e Ossos/metabolismo , Linhagem Celular , Cricetinae , Relação Dose-Resposta a Droga , Estrogênios/farmacologia , Meia-Vida , Humanos , Masculino , Camundongos , Ovariectomia , Hormônio Paratireóideo/farmacocinética , Transporte Proteico , Ratos , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Fatores de Tempo , beta-Arrestinas
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