Nmp4, a Regulator of Induced Osteoanabolism, Also Influences Insulin Secretion and Sensitivity

Bidwell, Joseph P.; Tersey, Sarah A.; Adaway, Michele; Bone, Robert N.; Creecy, Amy; Klunk, Angela; Atkinson, Emily G.; Wek, Ronald C.; Robling, Alexander G.; Wallace, Joseph M.; Evans‐Molina, Carmella

doi:10.1007/s00223-021-00903-7

Cited by 3 publications

(3 citation statements)

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“…( 35,37,42 ) Additionally, it has a significant impact on the activity of numerous secretory cells. ( 38,39,86 ) In our scaling factor hypothesis, Nmp4 actually suppresses the allocation of the secretory cell proteome during the transition from MSPC to osteoblast, targeted by Nmp4 fl/fl ;Prx1Cre + . Delaying the removal of Nmp4 until the mature osteoblast stage ( Nmp4 fl/fl ;BglapCre + ) may therefore be too late for having any influence on establishing the capacity of the osteoblast secretory floorplan, the primary bone former.…”

Section: Discussionmentioning

confidence: 91%

“…(32)(33)(34)(35)(36)(37) These mice are healthy under normal vivarium conditions and indeed are resistant to disease severity during influenza A viral infection and are less sensitive to high-fat diet (HFD)-induced weight gain, increases in % fat mass, and decreases in glucose tolerance and insulin sensitivity. (38,39) The Nmp4 gene is a Cys 2 His 2 zinc finger transcription factor expressed in all tissues. (40) Loss of Nmp4 increases the number of bone marrow osteoprogenitors in experimental mice.…”

Section: Introductionmentioning

confidence: 99%

“…(42,43) Remarkably, Nmp4 governs professional secretory cells in a tissue-specific manner. Whereas it suppresses osteoprogenitor/ osteoblast secretion of bone matrix, (37) it supports pancreatic beta cell insulin secretion (39) as well as lung epithelial cell production and release of the chemokines CCL2 and CXCL1 and bone marrow-derived macrophage release of CCL7. (38) Osteoprogenitors, osteoblasts, and osteocytes all are secretory cells controlling bone homeostasis and bone remodeling.…”

Section: Introductionmentioning

confidence: 99%

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Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation

Atkinson

Adaway

Horan

et al. 2020

Journal of Bone and Mineral Research

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Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis, yet FDA‐approved osteoanabolics, eg, parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice exhibit enhanced PTH‐induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4‐floxed (Nmp4fl/fl) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+ to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+ targeting mature osteoblasts, and (iii) Dmp1Cre+ to disable Nmp4 in osteocytes. Virgin female Cre+ and Cre− mice (10 weeks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1‐34 at 30 μg/kg or vehicle for 4 weeks or 7 weeks. Skeletal response was assessed using dual‐energy X‐ray absorptiometry, micro‐computed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4fl/fl;Prx1Cre+ mice virtually phenocopied the global Nmp4−/− skeleton in the femur, ie, a mild baseline phenotype but significantly enhanced PTH‐induced increase in femur trabecular bone volume/total volume (BV/TV) compared with their Nmp4fl/fl;Prx1Cre− controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl;BglapCre+) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl;Dmp1Cre+) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4−/− Prx1‐expressing MSPCs drive the improved response to PTH therapy and that this gene has stage‐specific effects on osteoanabolism. © 2022 American Society for Bone and Mineral Research (ASBMR).

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Section: Discussionmentioning

confidence: 91%