Loss of Nmp4 enhances bone gain from sclerostin antibody administration

Crystal Korff; Michele Adaway; Emily G Atkinson; Daniel J Horan; Angela Klunk; Brandy Suarez Silva; Teresita Bellido; Lilian I Plotkin; Alexander G Robling; Joseph P Bidwell

doi:10.1016/j.bone.2023.116891

Loss of Nmp4 enhances bone gain from sclerostin antibody administration

Bone. 2023 Dec:177:116891. doi: 10.1016/j.bone.2023.116891. Epub 2023 Sep 3.

Authors

Affiliations

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA.
² Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA.
³ Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA.
⁴ Department of Biochemistry and Molecular Biology, IUSM, USA.
⁵ Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72205, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
⁶ Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA; Indiana Center for Musculoskeletal Health, IUSM, USA.
⁷ Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, IUSM, USA. Electronic address: jbidwell@iupui.edu.

PMID: 37660938
PMCID: PMC10591883 (available on 2024-12-01)
DOI: 10.1016/j.bone.2023.116891

Abstract

Severe osteoporosis is often treated with one of three Food and Drug Administration (FDA)-approved osteoanabolics. These drugs act by (1) parathyroid hormone (PTH) receptor stimulation using analogues to PTH (teriparatide) or PTH-related peptide (abaloparatide) or by (2) monoclonal antibody neutralization of sclerostin, an innate Wnt inhibitor (Scl-mAb, romosozumab-aqqg). The efficacies of both strategies wane over time. The transcription factor Nmp4 (Nuclear Matrix Protein 4) is expressed in all tissues yet mice lacking this gene are healthy and exhibit enhanced PTH-induced bone formation. Conditional deletion of Nmp4 in mesenchymal stem progenitor cells (MSPCs) phenocopies the elevated response to PTH in global Nmp4^-/- mice. However, targeted deletion in later osteoblast stages does not replicate this response. In this study we queried whether loss of Nmp4 improves Scl-mAb potency. Experimental cohorts included global Nmp4^-/- and Nmp4^+/+ littermates and three conditional knockout models. Nmp4-floxed (Nmp4^fl/fl) mice were crossed with mice harboring one of three Cre-drivers (i) Prx1Cre+ targeting MSPCs, (ii) BglapCre+ (mature osteocalcin-expressing osteoblasts), and (iii) Dmp1Cre+ (osteocytes). Female mice were treated with Scl-mAb or 0.9 % saline vehicle for 4 or 7 weeks from 10 weeks of age. Skeletal response was assessed using micro-computed tomography, dual-energy X-ray absorptiometry, bone histomorphometry, and serum analysis. Global Nmp4^-/- mice exhibited enhanced Scl-mAb-induced increases in trabecular bone in the femur and spine and a heightened increase in whole body areal bone mineral density compared to global Nmp4^+/+ controls. This improved Scl-mAb potency was primarily driven by enhanced increases in bone formation. Nmp4^fl/fl;PrxCre+ mice showed an exaggerated Scl-mAb-induced increase in femoral bone but not in the spine since Prrx1 is not expressed in vertebra. The Nmp4^fl/fl;BglapCre+ and Nmp4^fl/fl;Dmp1Cre+ mice did not exhibit an improved Scl-mAb response. We conclude that Nmp4 expression in MSPCs interferes with the bone anabolic response to anti-sclerostin therapy.

Keywords: Bone anabolism; Osteoanabolics; Osteoporosis; Romosozumab-aqqg.

Abstract

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