Sclerostin Antibody Treatment Improves Implant Fixation in a Model of Severe Osteoporosis

Virdi, Amarjit S.; Irish, John; Sena, Kotaro; Liu, Min; Ke, Hua Zhu; McNulty, Margaret A.; Sumner, Dale R.

doi:10.2106/jbjs.n.00654

Cited by 55 publications

(75 citation statements)

References 43 publications

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“…On one hand, this gives support to the hypothesis that bone, which produces almost all the available sclerostin, may play a role also in glucose metabolism and insulin resistance (8,32,35). On the other hand, it can be speculated that anti-sclerostin antibody treatment, which is a promising option for severe osteoporosis and surgical implant fixation, might have a role in T2DM treatment (36).…”

Section: Discussionmentioning

confidence: 57%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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OBJECTIVEA gene mutation of the Wnt/b-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/b-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and b-cell function. RESEARCH DESIGN AND METHODSWe performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTSSclerostin levels were higher in IGR compared with NGT (50.8 6 2.4 vs. 38.7 6 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = 20.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = 20.52 and r = 20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with b-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r 2 associated with HOMA-IR (r 2 change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r 2 change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONSSclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.

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Section: Discussionmentioning

confidence: 57%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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“…In unloading models, such as in tail suspension, sclerostin expression levels increase, thereby inhibiting the Wnt signaling pathway, inducing apoptosis, suppressing osteoblast activity and decreasing the bone mass (20). Therefore, the current strategy of anti-sclerostin treatment for bone loss-associated diseases, as a potential therapeutic approach, has been investigated by numerous studies (33)(34)(35)(36).…”

Section: A B Discussionmentioning

confidence: 99%

Sclerostin is essential for alveolar bone loss in occlusal hypofunction

Wang

Sun

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Bone loss is caused by occlusal hypofunction and is a serious health concern. This is particularly true of tooth loss, which is common in the elderly. However, the cellular and molecular mechanisms underlying bone loss have yet to be fully elucidated. Sclerostin and Wnt/β-catenin signaling have previously been reported to serve important roles in regulating bone remodeling. Therefore, the present study aimed to investigate the involvement of sclerostin and Wnt/β-catenin signaling in occlusal hypofunction-induced alveolar bone remodeling. The unilateral maxillary molars of 14 male Sprague-Dawley rats were extracted in order to establish a model of occlusal hypofunction. For each rat, the non-extraction side was treated as the control group for comparisons with the extraction side. At 8 weeks after tooth extraction, the rats were sacrificed and alveolar bone specimens were harvested for X-ray radiography, micro-computed tomography (CT) and histological and immunohistochemical examinations. Bone loss and architecture deterioration were observed at the occlusal hypofunction side. The bone mineral density was markedly decreased and the ratio of bone volume to total volume was significantly decreased at the hypofunction side, as compared with the control side (P<0.001). In addition, the number of osteoclasts at the hypofunction side were significantly increased compared with that in the control side (P<0.001), as demonstrated using tartrate-resistant acid phosphatase staining. Furthermore, the protein expression levels of sclerostin and receptor activator of nuclear factor-κB ligand were increased, whereas those of β-catenin were decreased, at the hypofunction side when compared with the control side. In conclusion, the results of the present study suggested that occlusal hypofunction-induced bone loss may be associated with upregulated expression of sclerostin, which, in turn, may inhibit the activity of the Wnt/β-catenin signaling pathway. IntroductionTooth loss is a common and serious health concern, particularly in the elderly. Although the incidence of tooth loss has declined in industrialized countries, the goal established by the World Health Organization of retaining 20 teeth at the age of 80 years has not been widely achieved (1,2). Mechanical stress has a crucial role in bone remodeling (3,4) and bone loss may occur as a result of reduced mechanical force, which is defined as disuse osteoporosis (5). Occlusal hypofunction due to tooth loss has a negative impact on jaw bone homeostasis (6). Tooth loss may lead to a reduced bite force in the antagonistic tooth and underlying alveolar bone during chewing. A lack of functional occlusion may induce active alveolar bone loss, including decreasing bone mass and volume (7,8). In addition, in certain pathological conditions, such as estrogen deficiency, functional occlusion has been revealed to slow down the rate of bone loss (9), whereas occlusal hypofunction was reported to accelerate bone loss (10,11). However, the cellular and molecular mechanisms under...

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“…The outcomes of the mechanical marrow ablation model are reproducible and applicable to the study of intramembranous bone regeneration 3,4,16 and bone-implant fixation in orthopedic 9,18,19 and dental 22,23 applications. As a technique with a bone regeneration end point (Figure 4), the marrow ablation model induces trabecular bone formation within the intramedullary canal in regions that, under normal conditions, lack trabecular bone.…”

Section: Discussionmentioning

confidence: 96%

“…Depending upon the study, the opening with implant present can be filled with bone wax. 19 A third scenario uses a larger hand drill with a 2.0 mm drill bit to widen the distal 5 mm of the ablation site, followed by implant placement. 20 This widened portion of the canal and the lack of bone wax allow for exposure of the ablation site to the joint space and is used in a model where particles are introduced into the joint space to mimic particle-induced peri-implant osteolysis.…”

Section: Intramembranous Bone Regeneration and Implant Placement MM Mmentioning

confidence: 99%

“…14,15 Model choice depends upon the type of bone formation to be studied, as well as the importance of loadbearing, skeletal region and ability to translate to the clinic. The marrow ablation model is primarily used for two main purposes: (1) as a model for intramembranous bone regeneration 3,4,16,17 and (2) as a model to study implant fixation in orthopedics 9,[18][19][20][21] and dentistry. 22,23 Therefore, the model is of interest to orthopedic and dental research, including biomaterial specialists, implant designers and molecular biologists as well as the field of regenerative medicine.…”

Section: Introductionmentioning

confidence: 99%

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Intramembranous bone regeneration and implant placement using mechanical femoral marrow ablation: rodent models

et al. 2016

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In this paper, we provide a detailed protocol for a model of long bone mechanical marrow ablation in the rodent, including surgical procedure, anesthesia, and pre-and post-operative care. In addition, frequently used experimental end points are briefly discussed. This model was developed to study intramembranous bone regeneration following surgical disruption of the marrow contents of long bones. In this model, the timing of the appearance of bone formation and remodeling is well-characterized and therefore the model is well-suited to evaluate the in vivo effects of various agents which influence these processes. When biomaterials such as tissue engineering scaffolds or metal implants are placed in the medullary cavity after marrow ablation, end points relevant to tissue engineering and implant fixation can also be analyzed. By sharing a detailed protocol, we hope to improve inter-laboratory reproducibility.

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Sclerostin Antibody Treatment Improves Implant Fixation in a Model of Severe Osteoporosis

Abstract: Systemic administration of anti-sclerostin antibodies might be a useful strategy in total joint replacement when bone mass is deficient.

Cited by 55 publications

References 43 publications

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Sclerostin is essential for alveolar bone loss in occlusal hypofunction

Intramembranous bone regeneration and implant placement using mechanical femoral marrow ablation: rodent models

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