Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats

Li, Xiaodong; Warmington, Kelly; Niu, Qing-Tian; Asuncion, Frank; Barrero, Mauricio; Grisanti, Mario; Dwyer, Denise; Stouch, Brian; Thway, Theingi M.; Stolina, Marina; Ominsky, Michael S.; Kostenuik, Paul J.; Simonet, W S; Pászty, Chris; Ke, Hua Zhu

doi:10.1002/jbmr.182

Cited by 214 publications

(215 citation statements)

References 37 publications

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“…Nonetheless, the armamentarium of anabolic therapies is restricted to just recombinant human parathyroid hormone. Targeting the osteocyte toward an anabolic response may provide a viable alternative, which could be achieved either by stimulating the Wnt pathway, an approach that is currently underway (53)(54)(55)(56), or, as we suggest, by stimulating Notch signaling.…”

Section: Discussionmentioning

confidence: 99%

Anabolic actions of Notch on mature bone

Liu

Ping

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.

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Section: Discussionmentioning

confidence: 99%

Anabolic actions of Notch on mature bone

Liu

Ping

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The administration of Wnt ligand [30] or an antibody which blocks sclerostin leads to an increase in bone mass and strength in rodents [21,[31][32][33] and monkeys [33][34]. Both bone formation in response to trauma and in animals with induced osteoporosis was increased.…”

Section: Discussionmentioning

confidence: 99%

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Agholme

Isaksson

Kuhstoss

et al. 2011

Bone

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The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unknown if it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, µCT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botullinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233 %. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

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“…As the Wnt ligands, as well as the downstream signaling molecules GSK3b and b-catenin, are rather ubiquitous and have been implicated in cancer progression, these are less attractive targets despite their obvious anabolic potential (169,170). On the other hand, the identification of the soluble inhibitors of Wnt signaling, such as sclerostin, DKK1-4, WIF, and sFRPs, identified a series of interesting targets for antibody and small-molecule inhibitor therapy (169), and especially sclerostin that appears rather bone specific and DKK1 have been explored extensively (171,172,173,174).…”

Section: The Wnt/lrp5 Systemmentioning

confidence: 99%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats

Cited by 214 publications

References 37 publications

Anabolic actions of Notch on mature bone

Anabolic actions of Notch on mature bone

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

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