Loss of <em>Nmp4</em> enhances bone gain from sclerostin antibody administration

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

Affiliations

¹Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA

²Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA

³Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA

⁴Department of Biochemistry and Molecular Biology, IUSM, USA

⁵Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72205, USA

⁶Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA

⁷Indiana Center for Musculoskeletal Health, IUSM, USA

⁸Current address: IU Ventures 642 N. Madison St, Suite 113 Bloomington, IN 47404, USA

Abstract and keywords

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

Links

DOI: 10.1016/j.bone.2023.116891

PubMed: 37660938

WoS: 001088801000001

History

Received: 2023-07-5

Revised: 2023-08-22

Accepted: 2023-08-30

Online: 2023-09-3

Cited Works (14)

Year	Entry
2012	Kim SW, Pajevic PD, Selig M, Barry KJ, Yang J-Y, Shin CS, Baek W-Y, Kim J-E, Kronenberg HM. Intermittent parathyroid hormone administration converts quiescent lining cells to active osteoblasts. J Bone Miner Res. October 2012;27(10):2075-2084.
2022	Poole KES, Treece GM, Pearson RA, Gee AH, Bolognese MA, Brown JP, Goemaere S, Grauer A, Hanley DA, Mautalen C, Recknor C, Yang Y-C, Rojeski M, Libanati C, Whitmarsh T. Romosozumab enhances vertebral bone structure in women with low bone density. J Bone Miner Res. February 2022;37(2):256-264.
2014	Ominsky MS, Niu Q-T, Li C, Li X, Ke HZ. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J Bone Miner Res. June 2014;29(6):1424-1430.
2005	Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. May 20, 2005;280(20):19883-19887.
2005	Glass DA II, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. May 2005;8(5):751-764.
2021	Lim K-E, Bullock WA, Horan DJ, Williams BO, Warman ML, Robling AG. Co-deletion of Lrp5 and Lrp6 in the skeleton severely diminishes bone gain from sclerostin antibody administration. Bone. February 2021;143:115708.
2005	Semënov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. July 22, 2005;280(29):26770-26775.
2021	Balani DH, Trinh S, Xu M, Kronenberg HM. Sclerostin antibody administration increases the numbers of Sox9creER+ skeletal precursors and their progeny. J Bone Miner Res. April 2021;36(4):757-767.
2011	Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. January 2011;26(1):19-26.
2002	Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ. Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer. genesis. June 2002;33(2):77-80.
2020	Lv F, Cai X, Yang W, Gao L, Chen L, Wu J, Ji L. Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: systematic review and meta-analysis. Bone. January 2020;130:115121.
2020	Conley RB, Adib G, Adler RA, Åkesson KE, Alexander IM, Amenta KC, Blank RD, Brox WT, Carmody EE, Chapman‐Novakofski K, Clarke BL, Cody KM, Cooper C, Crandall CJ, Dirschl DR, Eagen TJ, Elderkin AL, Fujita M, Greenspan SL, Halbout P, Hochberg MC, Javaid M, Jeray KJ, Kearns AE, King T, Koinis TF, Koontz JS, Kužma M, Lindsey C, Lorentzon M, Lyritis GP, Michaud LB, Miciano A, Morin SN, Mujahid N, Napoli N, Olenginski TP, Puzas JE, Rizou S, Rosen CJ, Saag K, Thompson E, Tosi LL, Tracer H, Khosla S, Kiel DP. Secondary fracture prevention: consensus clinical recommendations from a multistakeholder coalition. J Bone Miner Res. January 2020;35(1):36-52.
1999	Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest. August 1999;104(4):439-446.
2017	Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, Maddox J, Fan M, Meisner PD, Grauer A. Romosozumab or alendronate for fracture prevention in women with osteoporosis. NEJM. October 12, 2017;377(15):1417-1427.