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

Atkinson, Emily G.; Adaway, Michele; Horan, Daniel J.; Korff, Crystal; Klunk, Angela; Orr, Ashley L.; Ratz, None Katherine; Bellido, Teresita; Plotkin, Lilian I.; Robling, Alexander G.; Bidwell, Joseph P.

doi:10.1002/jbmr.4732

Cited by 3 publications

(1 citation statement)

References 107 publications

(225 reference statements)

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“…These findings suggest that Nmp4 in Prx1-expressing SSCs plays a key role in regulating the improved response to PTH therapy. Additionally, Nmp4 exhibits stage-specific effects on osteoanabolism, with its influence varying depending on the specific cell type and stage of bone development [ 85 ].…”

Section: The Direct Interactions Of Pth With Bm Cellsmentioning

confidence: 99%

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche

Liu,

Rosen

2024

Cells

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Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH’s role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH—catabolic and anabolic—on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH’s multifaceted influence on bone health.

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Section: The Direct Interactions Of Pth With Bm Cellsmentioning

confidence: 99%

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche

Liu,

Rosen

2024

Cells

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NMP4, an Arbiter of Bone Cell Secretory Capacity and Regulator of Skeletal Response to PTH Therapy

et al. 2023

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Deletion of the auxiliary α2δ1 voltage sensitive calcium channel subunit in osteocytes and late-stage osteoblasts impairs femur strength and load-induced bone formation in male mice

Wright,

Lewis,

Semon

et al. 2024

Journal of Bone and Mineral Research

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Osteocytes sense and respond to mechanical force by controlling the activity of other bone cells. However, the mechanisms by which osteocytes sense mechanical input and transmit biological signals remain unclear. Voltage-sensitive calcium channels (VSCCs) regulate calcium (Ca2+) influx in response to external stimuli. Inhibition or deletion of VSCCs impairs osteogenesis and skeletal responses to mechanical loading. VSCC activity is influenced by its auxiliary subunits, which bind the channel’s α1 pore-forming subunit to alter intracellular Ca2+ concentrations. The α2δ1 auxiliary subunit associates with the pore-forming subunit via a glycosylphosphatidylinositol (GPI) anchor and regulates the channel’s calcium-gating kinetics. Knockdown of α2δ1 in osteocytes impairs responses to membrane stretch, and global deletion of α2δ1 in mice results in osteopenia and impaired skeletal responses to loading in vivo. Therefore, we hypothesized that the α2δ1 subunit functions as a mechanotransducer, and its deletion in osteocytes would impair skeletal development and load-induced bone formation. Mice (C57BL/6) with LoxP sequences flanking Cacna2d1, the gene encoding α2δ1, were crossed with mice expressing Cre under the control of the Dmp1 promoter (10 kb). Deletion of α2δ1 in osteocytes and late-stage osteoblasts decreased femoral bone quantity (p<0.05) by DXA, reduced relative osteoid surface (p<0.05), and altered osteoblast and osteocyte regulatory gene expression (p<0.01). Cacna2d1f/f, Cre+ male mice displayed decreased femoral strength and lower 10-wk cancellous bone in vivo μCT measurements at the proximal tibia (p<0.01) compared to controls, whereas Cacna2d1f/f, Cre+ female mice showed impaired 20-wk cancellous and cortical bone ex vivo μCT measurements (p<0.05) versus controls. Deletion of α2δ1 in osteocytes and late-stage osteoblasts suppressed load-induced calcium signaling in vivo and decreased anabolic responses to mechanical loading in male mice, demonstrating decreased mechanosensitivity. Collectively, the α2δ1 auxiliary subunit is essential for the regulation of osteoid-formation, femur strength, and load-induced bone formation in male mice.

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

Cited by 3 publications

References 107 publications

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche

NMP4, an Arbiter of Bone Cell Secretory Capacity and Regulator of Skeletal Response to PTH Therapy

Deletion of the auxiliary α2δ1 voltage sensitive calcium channel subunit in osteocytes and late-stage osteoblasts impairs femur strength and load-induced bone formation in male mice

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