The Notch pathway regulates the bone gain induced by PTH anabolic signaling

Delgado‐Calle, Jesús; McAndrews, Kevin; Wu, Gerald J.; Orr, Ashley L; Ferrari, Adam J.; Tu, Xiaolin; Srinivasan, Venkatesan; Roodman, G. David; Ebetino, Frank H.; Boeckman, Robert K.; Bellido, Teresita

doi:10.1096/fj.202101807r

Cited by 9 publications

(9 citation statements)

References 44 publications

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“…The dose of PTH (100 μg•kg −1 per day or 24 pmol•g −1 per day) was chosen to attain optimal responses based on earlier studies. [39][40][41][42] The dose of ABL (95 μg•kg −1 per day or 24 pmol•g −1 per day) was chosen to allow a direct mole to mole comparison with PTH. Half dose of ABL (47.5 μg•kg −1 per day or 12 pmol•g −1 per day) was also used based on our earlier study with the PTHrP (1-37) and diabetic mice 19 and studies using ABL in ovariectomized rats.…”

Section: Animalsmentioning

confidence: 99%

Reversal of the diabetic bone signature with anabolic therapies in mice

Marino

Akel

et al. 2023

Bone Res

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The mechanisms underlying the bone disease induced by diabetes are complex and not fully understood; and antiresorptive agents, the current standard of care, do not restore the weakened bone architecture. Herein, we reveal the diabetic bone signature in mice at the tissue, cell, and transcriptome levels and demonstrate that three FDA-approved bone-anabolic agents correct it. Diabetes decreased bone mineral density (BMD) and bone formation, damaged microarchitecture, increased porosity of cortical bone, and compromised bone strength. Teriparatide (PTH), abaloparatide (ABL), and romosozumab/anti-sclerostin antibody (Scl-Ab) all restored BMD and corrected the deteriorated bone architecture. Mechanistically, PTH and more potently ABL induced similar responses at the tissue and gene signature levels, increasing both formation and resorption with positive balance towards bone gain. In contrast, Scl-Ab increased formation but decreased resorption. All agents restored bone architecture, corrected cortical porosity, and improved mechanical properties of diabetic bone; and ABL and Scl-Ab increased toughness, a fracture resistance index. Remarkably, all agents increased bone strength over the healthy controls even in the presence of severe hyperglycemia. These findings demonstrate the therapeutic value of bone anabolic agents to treat diabetes-induced bone disease and suggest the need for revisiting the approaches for the treatment of bone fragility in diabetes.

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Section: Animalsmentioning

confidence: 99%

Reversal of the diabetic bone signature with anabolic therapies in mice

Marino

Akel

et al. 2023

Bone Res

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“…The involvement of the Notch signalling pathway in the osteoblast-Ti interaction is underexplored, despite its well-known participation in osteogenesis [ 31 , 66 , 67 ]. The Ti surface hydrophilicity was observed to favour bone formation by acting on several signalling pathways involved in proliferation and osteoblast precursor differentiation, including Notch signalling [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Modulation of the Hedgehog and Notch Signaling Pathways on Osteoblast Differentiation Induced by Titanium with Nanotopography

Souza

Adolpho

Lopes

et al. 2023

JFB

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Background: The events of bone formation and osteoblast/titanium (Ti) interactions may be affected by Hedgehog and Notch signalling pathways. Herein, we investigated the effects of modulation of these signalling pathways on osteoblast differentiation caused by the nanostructured Ti (Ti-Nano) generated by H2SO4/H2O2. Methods: Osteoblasts from newborn rat calvariae were cultured on Ti-Control and Ti-Nano in the presence of the Hedgehog agonist purmorphamine or antagonist cyclopamine and of the Notch antagonist N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or agonist bexarotene. Osteoblast differentiation was evaluated by alkaline phosphatase activity and mineralization, and the expression of Hedgehog and Notch receptors was also evaluated. Results: In general, purmorphamine and DAPT increased while cyclopamine and bexarotene decreased osteoblast differentiation and regulated the receptor expression on both Ti surfaces, with more prominent effects on Ti-Nano. The purmorphamine and DAPT combination exhibited synergistic effects on osteoblast differentiation that was more intense on Ti-Nano. Conclusion: Our results indicated that the Hedgehog and Notch signalling pathways drive osteoblast/Ti interactions more intensely on nanotopography. We also demonstrated that combining Hedgehog activation with Notch inhibition exhibits synergistic effects on osteoblast differentiation, especially on Ti-Nano. The uncovering of these cellular mechanisms contributes to create strategies to control the process of osseointegration based on the development of nanostructured surfaces.

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“…In contrast, other studies have reported that prolonged iPTH treatment boosts the expression of Notch pathway components like Notch1 in osteocytes, contributing to a reduced bone resorption and increased bone formation [ 210 ]. The activation of Notch1 promotes the expression of OPG and also inhibits Sost in osteocytes, which increases bone formation [ 211 ].…”

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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The Notch pathway regulates the bone gain induced by PTH anabolic signaling

Cited by 9 publications

References 44 publications

Reversal of the diabetic bone signature with anabolic therapies in mice

Reversal of the diabetic bone signature with anabolic therapies in mice

Effects of Modulation of the Hedgehog and Notch Signaling Pathways on Osteoblast Differentiation Induced by Titanium with Nanotopography

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

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