Targeting cellular stress in vitro improves osteoblast homeostasis, matrix collagen content and mineralization in two murine models of osteogenesis imperfecta

Garibaldi, Nadia; Contento, Barbara Maria; Babini, Gabriele; Morini, Jacopo; Siciliani, Stella; Biggiogera, Marco; Raspanti, Mario; Marini, Joan C.; Rossi, Antonio; Forlino, Antonella; Besio, Roberta

doi:10.1016/j.matbio.2021.03.001

Cited by 22 publications

(27 citation statements)

References 91 publications

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“…We have also given some examples of indirect protective effect of RA on collagen by influencing the factors regulating its biosynthesis, e.g., extracellular signal-regulated protein kinases 1 and 2 [ 36 ]. In the current study we also proved the beneficial effect of 100 µM RA which prevented changes induced by BP-3 in the expression of other important proteins such as chaperones (PDI, HSP47) enzymes (GLT25D1, MMP-1, MMP-2), sulfated GAGs and decorin, involved in the modification, folding, structure stabilization, secretion, fibrillogenesis, and remodelling of collagen [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Normalizing or significantly reducing these adverse changes in the presence of RA has prevented BP-3-induced cellular stress, which either activates UPR and partially restores cell homeostasis but may also lead to cell apoptosis [ 47 , 48 , 51 ].…”

Section: Discussionsupporting

confidence: 53%

“…Type I collagen biosynthesis is a very complex process which consists of a series of post-translational modifications, joining three procollagen chains (two α1 and one α2) and folding them into a triple right-handed helix, secretion into the extracellular space and formation of fibrils. These steps require the coordinated action of many rough endoplasmic reticulum (ER) molecules, including enzymes and chaperones, and the importance of these proteins in collagen biosynthesis is evidenced by many diseases, including osteogenesis imperfecta (OI) caused by their mutations [ 45 , 46 , 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…Two forms of β(1-O) galactosyltransferase (GLT25D1 and GLT25D2) have been identified, while O-linked glycosylation of collagen type I is catalyzed mainly by GLT25D1 [ 49 ]. In OI, the intracellular retention is usually caused by abnormal hydroxylation and excessive glycosylation of type I collagen, which disrupts collagen secretion, and induces ER stress and subsequent the unfolded protein response (UPR) [ 47 , 48 ]. In our study the observed collagen retention was accompanied by the increase in the expression of the collagen chaperone HSP47 at both the mRNA and protein levels.…”

Section: Discussionmentioning

confidence: 99%

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The Beneficial Effect of Rosmarinic Acid on Benzophenone-3-Induced Alterations in Human Skin Fibroblasts

Gavin

Sutkowska-Skolimowska

2021

IJMS

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Benzophenone-3 (BP-3) is one of the most widely used chemical sunscreens. The results of many in vitro and in vivo tests confirm its high percutaneous penetration and systemic absorption, which question the safety of its wide use. The aim of our research was to assess the effect of this compound on components of the skin extracellular matrix, and to investigate whether rosmarinic acid (RA) could reduce BP-3-induced changes in human skin fibroblasts. BP-3 used at concentrations of 0.1–100 µM caused a number of unfavorable changes in the level of type I collagen, decorin, sulfated glycosaminoglycans, hyaluronic acid, elastin, and expression or activity of matrix metalloproteinases (MMP-1, MMP-2), elastase and hyaluronidase. Moreover, the intracellular retention of collagen was accompanied by changes in the expression of proteins modifying and controlling the synthesis and secretion of this protein. Most importantly, RA at a concentration of 100 µM significantly reduced or completely abolished the adverse effects of BP-3. Based on these findings, it can be concluded that this polyphenol may provide effective protection against BP-3-induced disturbances in skin cells, which may have important clinical implications.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Beneficial Effect of Rosmarinic Acid on Benzophenone-3-Induced Alterations in Human Skin Fibroblasts

Gavin

Sutkowska-Skolimowska

2021

IJMS

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“…A recently proposed attractive target of OI therapy is ER stress caused by intracellular retention of mutant collagen in osteoblasts and fibroblasts [67][68][69][70]. The use of the FDA-approved chemical chaperone 4-phenylbutyrate (4-PBA), which additionally exhibits histone deacetylase inhibitor activity, ameliorated cell homeostasis in fibroblasts from dominant and recessive OI patients and in the Chihuahua zebrafish model of the classical dominant OI [67][68][69].…”

Section: Counteraction Of Er Stress and Uprmentioning

confidence: 99%

“…Treatment with 4-PBA has been also shown to alleviate cellular stress by restoring the normal size of ER cisternae, normalizing the expression of the apoptosis marker caspase-3 and decreasing the activation of the unfolded protein response (UPR) in Brtl and Amish mouse models. In addition, the drug promotes collagen secretion and its incorporation into the ECM [70]. Treatment with 4-PBA of fibroblasts from dominant OI patients with α1(I) mutations facilitated collagen folding and secretion, decreased the expression of eukaryotic translation initiation factor 2 alpha kinase 3 (PERK) and reduced the activation of apoptosis [67].…”

Section: Counteraction Of Er Stress and Uprmentioning

confidence: 99%

Osteogenesis Imperfecta: Current and Prospective Therapies

et al. 2021

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Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI.

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Endothelial Cell‐Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis

Wu,

Hu,

Jiang

et al. 2023

Advanced Science

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Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)‐specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC‐specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2‐deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.

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Targeting cellular stress in vitro improves osteoblast homeostasis, matrix collagen content and mineralization in two murine models of osteogenesis imperfecta

Cited by 22 publications

References 91 publications

The Beneficial Effect of Rosmarinic Acid on Benzophenone-3-Induced Alterations in Human Skin Fibroblasts

The Beneficial Effect of Rosmarinic Acid on Benzophenone-3-Induced Alterations in Human Skin Fibroblasts

Osteogenesis Imperfecta: Current and Prospective Therapies

Endothelial Cell‐Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis

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