Improving Bone Health by Optimizing the Anabolic Action of <scp>Wnt</scp> Inhibitor Multitargeting

Choi, Roy B; Bullock, Whitney A.; Hoggatt, April M.; Loots, Gabriela G.; Genetos, Damian C.

doi:10.1002/jbm4.10462

Cited by 7 publications

(13 citation statements)

References 23 publications

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“…Collection of repeated DXA measurements on mice are described and validated elsewhere [ 17 ]. Briefly, isoflurane-anesthetized mice were scanned on a PIXImus II (GE Lunar) densitometer at the beginning of the treatment period (1 st week) and again at the terminal period.…”

Section: Methodsmentioning

confidence: 99%

“…Formalin-fixed femora and 5 th lumbar vertebrae (L5) were scanned, reconstructed, and analyzed on a Scanco µCT-35 as previously described [ 17 ]. 10-μm resolution, 50-kV peak tube potential and 151-ms integration time were used.…”

Section: Methodsmentioning

confidence: 99%

“…Mice were sacrificed 3 days after the alizarin label. After sacrifice, the femurs were processed for plastic-embedded histomorphometry and cut at midshaft for histological evaluation as previously described [ 17 ]. Briefly, periosteal and endocortical mineralizing surface (MS/BS, %), mineral apposition rates (MAR; µm/day) and bone formation rates (BFR/BS; μm 3 /μm 2 /yr) were calculated using the demeclocycline and calcein labels, measured over the entire periosteal and endocortical surfaces (not subregions) according to standard protocols [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

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Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton

Choi¹,

Hoggatt²,

Horan³

et al. 2022

Aging and disease

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Age-associated low bone mass disease is a growing problem in the US. Development of osteoanabolic therapies for treating skeletal fragility has lagged behind anti-catabolic therapies, but several bone-building molecules are clinically available. We reported previously that antibody-based neutralization of the Lrp5/Lrp6 inhibitor Dkk1 has minimal effects on bone gain, but can potentiate the already potent osteoanabolic effects of sclerostin inhibition (another Lrp5/Lrp6 inhibitor highly expressed by osteocytes). In this communication, we test whether an optimized ratio of sclerostin and Dkk1 antibodies (Scl-mAb and Dkk1-mAb, respectively), administered at low doses, can maintain the same bone-building effects as higher dose Scl-mAb, in adult (6 months of age) and aged (20 months of age) wild-type mice. A 3:1 dose of Scl-mAb:Dkk1-mAb at 12.5 mg/kg was equally efficacious as 25 mg/kg of Scl-mAb in both age groups, using radiographic (DXA, µCT), biomechanical, (3-point bending tests), and histological (fluorochrome-based bone formation parameters) outcome measures. For some bone properties, including trabecular thickness and bone mineral density in the spine, and endocortical bone formation rates in the femur, the 3:1 treatment was associated with significantly improved skeletal properties compared to twice the dose of Scl-mAb. Cortical porosity in aged mice was also reduced by both Scl-mAb and low-dose 3:1 treatment. Overall, both treatments were efficacious in the mature adult (6 mo.) and aged (20 mo.) skeletons, suggesting Wnt targeting is a viable strategy for improving skeletal fragility in the very old. Further, the data suggest that low dose of combination therapy can be at least equally efficacious as higher doses of Scl-mAb monotherapy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton

Choi¹,

Hoggatt²,

Horan³

et al. 2022

Aging and disease

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show abstract

“…Importantly, osteoanabolic effects of Dkk1-inhibition through treatment with anti-Dkk1 antibodies only results in bone formation when Sclerostin is deactivated (Witcher et al, 2018). Using this information, groups have tested therapeutic potential using combinatorial treatments of Wnt inhibitors, Dkk1 and Sclerostin (Choi et al, 2021). Choi et al determined significantly enhanced therapeutic efficacy using this dual antibody treatment on cancellous bone, but not for cortical bone (Choi et al, 2021).…”

Section: Other Antibody-based Approaches To Modulate Wntmentioning

confidence: 99%

“…Using this information, groups have tested therapeutic potential using combinatorial treatments of Wnt inhibitors, Dkk1 and Sclerostin (Choi et al, 2021). Choi et al determined significantly enhanced therapeutic efficacy using this dual antibody treatment on cancellous bone, but not for cortical bone (Choi et al, 2021).…”

Section: Other Antibody-based Approaches To Modulate Wntmentioning

confidence: 99%

Therapeutic approaches to activate the canonical Wnt pathway for bone regeneration

Nelson

Fontana

Miclau

et al. 2022

J Tissue Eng Regen Med

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Activation of the canonical Wingless‐related integration site (Wnt) pathway has been shown to increase bone formation and therefore has therapeutic potential for use in orthopedic conditions. However, attempts at developing an effective strategy to achieve Wnt activation has been met with several challenges. The inherent hydrophobicity of Wnt ligands makes isolating and purifying the protein difficult. To circumvent these challenges, many have sought to target extracellular inhibitors of the Wnt pathway, such as Wnt signaling pathway inhibitors Sclerostin and Dickkopf‐1, or to use small molecules, ions and proteins to increase target Wnt genes. Here, we review systemic and localized bioactive approaches to enhance bone formation or improve bone repair through antibody‐based therapeutics, synthetic Wnt surrogates and scaffold doping to target canonical Wnt. We conclude with a brief review of emerging technologies, such as mRNA therapy and Clustered Regularly Interspaced Short Palindromic Repeats technology, which serve as promising approaches for future clinical translation.

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Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice

Choi

Hoggatt

Horan

et al. 2020

Journal of Bone and Mineral Research

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The development of Wnt-based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co-inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild-type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties.

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Improving Bone Health by Optimizing the Anabolic Action of Wnt Inhibitor Multitargeting

Cited by 7 publications

References 23 publications

Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton

Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton

Therapeutic approaches to activate the canonical Wnt pathway for bone regeneration

Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice

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