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Article: Age-associated declining of the regeneration potential of skeletal stem/progenitor cells.

Mancinelli, Luigi / Intini, Giuseppe

2023 Volume 14, Page(s) 1087254

Abstract: Bone fractures represent a significant health burden worldwide, mainly because of the rising number of elderly people. As people become older, the risk and the frequency of bone fractures increase drastically. Such increase arises from loss of skeletal ... ...

Abstract	Bone fractures represent a significant health burden worldwide, mainly because of the rising number of elderly people. As people become older, the risk and the frequency of bone fractures increase drastically. Such increase arises from loss of skeletal integrity and is also associated to a reduction of the bone regeneration potential. Central to loss of skeletal integrity and reduction of regeneration potential are the skeletal stem/progenitor cells (SSPCs), as they are responsible for the growth, regeneration, and repair of the bone tissue. However, the exact identity of the SSPCs has not yet been determined. Consequently, their functions, and especially dysfunctions, during aging have never been fully characterized. In this review, with the final goal of describing SSPCs dysfunctions associated to aging, we first discuss some of the most recent findings about their identification. Then, we focus on how SSPCs participate in the normal bone regeneration process and how aging can modify their regeneration potential, ultimately leading to age-associated bone fractures and lack of repair. Novel perspectives based on our experience are also provided.
Language	English
Publishing date	2023-02-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1087254
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Article ; Online: Activation of creER recombinase in the mouse calvaria induces local recombination without effects on distant skeletal segments.

Hou, Jue / Lin, Charles P / Intini, Giuseppe

Scientific reports

2021 Volume 11, Issue 1, Page(s) 8214

Abstract: Conditional creER-mediated gene inactivation or gene induction has emerged as a robust tool for studying gene functions in mouse models of tissue development, homeostasis, and regeneration. Here, we present a method to conditionally induce cre ... ...

Abstract	Conditional creER-mediated gene inactivation or gene induction has emerged as a robust tool for studying gene functions in mouse models of tissue development, homeostasis, and regeneration. Here, we present a method to conditionally induce cre recombination in the mouse calvarial bone while avoiding systemic recombination in distal bones. To test our method, we utilized Prx1creER-egfp;td-Tomato mice and delivered 4-hydroxytamoxifen (4-OHT) to the mouse calvaria, subperiosteally. First, we showed that two calvaria subperiosteal injections of 10 µg of 4-OHT (3.3 mg of 4-OHT/kg of body weight) can induce local recombination as efficiently as two intraperitoneal systemic injections of 200 μg of tamoxifen (70 mg of tamoxifen/kg of body weight). Then, we studied the recombination efficiency of various subperiosteal calvaria dosages and found that two subperiosteal injections of 5 µg 4-OHT (1.65 mg of 4-OHT/kg of body weight) uphold the same recombination efficiency observed with higher dosages. Importantly, the result indicated that the low dosage does not induce significant systemic recombination in remote skeletal tissues. With the proposed local low dosage protocol, the recombination efficiency at the injection site (calvarial bone) reached 94%, while the recombination efficiency at the mandible and the digits was as low as the efficiency measured in control animals.
MeSH term(s)	Animals ; Bone and Bones/metabolism ; Enzyme Activation/genetics ; Female ; Gene Expression Regulation/drug effects ; Gene Targeting/methods ; Integrases/genetics ; Integrases/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Organ Specificity/genetics ; Promoter Regions, Genetic/drug effects ; Promoter Regions, Genetic/genetics ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism ; Recombination, Genetic/physiology ; Skull/metabolism ; Tamoxifen/analogs & derivatives ; Tamoxifen/pharmacology
Chemical Substances	Receptors, Estrogen ; Tamoxifen (094ZI81Y45) ; afimoxifene (17197F0KYM) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2021-04-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-87611-2
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Article ; Online: Avenues of research in dietary interventions to target tumor metabolism in osteosarcoma.

Leite, Taiana Campos / Watters, Rebecca Jean / Weiss, Kurt Richard / Intini, Giuseppe

Journal of translational medicine

2021 Volume 19, Issue 1, Page(s) 450

Abstract: Osteosarcoma (OS) is the most frequent primary bone cancer, affecting mostly children and adolescents. Although much progress has been made throughout the years towards treating primary OS, the 5-year survival rate for metastatic OS has remained at only ... ...

Abstract	Osteosarcoma (OS) is the most frequent primary bone cancer, affecting mostly children and adolescents. Although much progress has been made throughout the years towards treating primary OS, the 5-year survival rate for metastatic OS has remained at only 20% for the last 30 years. Therefore, more efficient treatments are needed. Recent studies have shown that tumor metabolism displays a unique behavior, and plays important roles in tumor growth and metastasis, making it an attractive potential target for novel therapies. While normal cells typically fuel the oxidative phosphorylation (OXPHOS) pathway with the products of glycolysis, cancer cells acquire a plastic metabolism, uncoupling these two pathways. This allows them to obtain building blocks for proliferation from glycolytic intermediates and ATP from OXPHOS. One way to target the metabolism of cancer cells is through dietary interventions. However, while some diets have shown anticancer effects against certain tumor types in preclinical studies, as of yet none have been tested to treat OS. Here we review the features of tumor metabolism, in general and about OS, and propose avenues of research in dietary intervention, discussing strategies that could potentially be effective to target OS metabolism.
MeSH term(s)	Adolescent ; Bone Neoplasms ; Cell Line, Tumor ; Cell Proliferation ; Glycolysis ; Humans ; Osteosarcoma
Language	English
Publishing date	2021-10-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-021-03122-8
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Article ; Online: Future approaches in periodontal regeneration: gene therapy, stem cells, and RNA interference.

Intini, Giuseppe

Dental clinics of North America

2010 Volume 54, Issue 1, Page(s) 141–155

Abstract: Periodontal disease is a major public health issue and the development of effective therapies to treat the disease and regenerate periodontal tissue is an important goal of today's medicine. This article highlights recent scientific advancements in gene ... ...

Abstract	Periodontal disease is a major public health issue and the development of effective therapies to treat the disease and regenerate periodontal tissue is an important goal of today's medicine. This article highlights recent scientific advancements in gene therapy, stem cell biology, and RNA interference with the intent of identifying their potential in periodontal tissue regeneration. Results from basic research, preclinical, and clinical studies indicate that these fields of research may soon contribute to more effective regenerative therapies for periodontal disease.
MeSH term(s)	Animals ; Bone Regeneration/genetics ; Genetic Therapy ; Humans ; Osteogenesis/genetics ; Periodontal Attachment Loss/surgery ; Periodontal Attachment Loss/therapy ; RNA Interference ; Regeneration/genetics ; Regeneration/physiology ; Stem Cell Transplantation
Language	English
Publishing date	2010-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	392075-6
ISSN	1558-0512 ; 0011-8532
ISSN (online)	1558-0512
ISSN	0011-8532
DOI	10.1016/j.cden.2009.09.002
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Article ; Online: Cryoglobulinemia: the "cold" problem in cardiac surgery, a single-center experience and a literature review.

Raimondo, Pasquale / Intini, Gianmarco / Lauletta, Gianfranco / Teora, Valentina / Lenoci, Sergio Domenico / Rubino, Giovanni / Villani, Maria Arcangela / Armenise, Agnese / Stripoli, Antonia / Colantuono, Giuseppe / Di Bari, Nicola / Fiore, Giuseppe / Paternoster, Gianluca / Grasso, Salvatore

Journal of anesthesia, analgesia and critical care

2024 Volume 4, Issue 1, Page(s) 6

Abstract: Cardiac surgery with cardiopulmonary bypass (CBP) is essential for different cardiac procedures in order to perform surgery with a clear sight field.To safely perform surgery with CPB and preserve brain, kidney, and patient tissue from ischemic damage, ... ...

Abstract	Cardiac surgery with cardiopulmonary bypass (CBP) is essential for different cardiac procedures in order to perform surgery with a clear sight field.To safely perform surgery with CPB and preserve brain, kidney, and patient tissue from ischemic damage, cold cardioplegia, and mild to deep hypothermia are induced during the operation.Cryoglobulinemia is a hematological/infective-related disease (in certain cases idiopathic) in which temperature-dependent antibodies tend to aggregate and form emboli in the vascular system causing tissue damage if exposed to low temperature.The patient with cryoglobulinemia (known and unknown) can be at risk of a major ischemic event during CPB and induced hypothermia.This article's aim is to evaluate the present scientific literature in order to understand how, in years, the therapeutic or preventive approach, is evolving, and to analyze and make improvements to the management of a cryoglobulinemic patient who must undergo elective or emergency cardiac surgery.In the last part of our article, we expose our single-center experience during a 32-month-long period of survey.In all cases, our medical team (anesthesiologists, perfusionists, and cardiac surgeons) opted for a normothermic cardiopulmonary bypass to lower the risk of cryoglobulin-associated complications.In our experience, along with therapeutic intervention to lower the cryoglobulin titer, normothermic management of cardiopulmonary bypass is as safe as hypothermic management.Notwithstanding our results, further studies with a larger population are needed to confirm this perioperative management in a cardiac surgery setting.
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Journal Article ; Review
ISSN	2731-3786
ISSN (online)	2731-3786
DOI	10.1186/s44158-024-00141-x
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Article ; Online: The use of platelet-rich plasma in bone reconstruction therapy.

Intini, Giuseppe

Biomaterials

2009 Volume 30, Issue 28, Page(s) 4956–4966

Abstract: The use of platelet-rich plasma (PRP) in bone reconstruction therapy was introduced in the late 1990s. Since then, many scientists and clinicians have employed it in orthopaedic and oral surgeries. Unfortunately, studies that analyze the use of PRP are ... ...

Abstract	The use of platelet-rich plasma (PRP) in bone reconstruction therapy was introduced in the late 1990s. Since then, many scientists and clinicians have employed it in orthopaedic and oral surgeries. Unfortunately, studies that analyze the use of PRP are somewhat controversial as some conclude that the use of PRP may favor bone regeneration and others conclude that the use of PRP is irrelevant. By listing and analyzing the biological effect that each factor released by the activated platelets can have in bone regeneration, the present review answers the question of why PRP may be useful in bone reconstruction therapy. Subsequently, by examining the studies that have both successfully and unsuccessfully utilized PRP, it suggests how PRP might be used in order to achieve successful results in orthopaedic and dental bone reconstruction surgeries.
MeSH term(s)	Animals ; Blood Platelets/metabolism ; Bone Regeneration ; Humans ; Oral Surgical Procedures ; Orthopedic Procedures ; Platelet-Derived Growth Factor/metabolism ; Platelet-Rich Plasma/metabolism ; Reconstructive Surgical Procedures
Chemical Substances	Platelet-Derived Growth Factor
Language	English
Publishing date	2009-10
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2009.05.055
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Article: PTH after Thyroidectomy as a Predictor of Post-Operative Hypocalcemia.

Metere, Alessio / Biancucci, Andrea / Natili, Andrea / Intini, Gianfrancesco / Graves, Claire E

Diagnostics (Basel, Switzerland)

2021 Volume 11, Issue 9

Abstract: Post-thyroidectomy hypocalcemia is a frequent complication with significant morbidity, and has been shown to increase hospital stay and readmission rates. The evaluation of serum parathyroid hormone (PTH) levels after thyroidectomy represents a reliable ... ...

Abstract	Post-thyroidectomy hypocalcemia is a frequent complication with significant morbidity, and has been shown to increase hospital stay and readmission rates. The evaluation of serum parathyroid hormone (PTH) levels after thyroidectomy represents a reliable method to predict post-thyroidectomy hypocalcemia, but it remains infrequently used. This retrospective study investigates serum PTH values 3 h after thyroidectomy as a predictor of hypocalcemia. In this study, we enrolled 141 patients aged between 27 and 71 years eligible for total thyroidectomy who presented with multinodular goiter, suspicious nodule on cytological examination, Graves' disease, or toxic multinodular goiter. Three hours after total thyroidectomy, 53 patients (37.6%) showed a reduction in serum PTH. Of these patients 75.5% developed hypocalcemia by 24 h after surgery and 100% were hypocalcemic after 48 h (
Language	English
Publishing date	2021-09-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics11091733
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Article ; Online: Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity.

Intini, Giuseppe / Nyman, Jeffry S

Bone

2015 Volume 75, Page(s) 151–160

Abstract: Bone fractures remain a serious health burden and prevention and enhanced healing of fractures have been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and ... ...

Abstract	Bone fractures remain a serious health burden and prevention and enhanced healing of fractures have been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1(+/-)) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2(c/c);Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1(+/-) mice were crossed with Bmp2(c/c);Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy.
MeSH term(s)	Animals ; Bone Morphogenetic Protein 2/metabolism ; Bone and Bones/diagnostic imaging ; Bone and Bones/metabolism ; Female ; Fracture Healing/physiology ; Haploinsufficiency ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Male ; Mice ; Mice, Transgenic ; Osteogenesis/physiology ; Signal Transduction/physiology ; X-Ray Microtomography
Chemical Substances	Bmp2 protein, mouse ; Bone Morphogenetic Protein 2 ; Dkk1 protein, mouse ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2015-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	632515-4
ISSN	1873-2763 ; 8756-3282
ISSN (online)	1873-2763
ISSN	8756-3282
DOI	10.1016/j.bone.2015.01.008
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Article ; Online: Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.

Intini, G / Katsuragi, Y / Kirkwood, K L / Yang, S

Advances in dental research

2014 Volume 26, Issue 1, Page(s) 38–46

Abstract: This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and ... ...

Abstract	This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of supplementation.
MeSH term(s)	Alveolar Bone Loss ; Bone Resorption ; Calcium/administration & dosage ; Female ; Humans ; Immunity, Innate ; Isoflavones/administration & dosage ; Middle Aged ; Postmenopause ; RGS Proteins/physiology ; Signal Transduction ; Stem Cells/cytology ; Vitamin D/administration & dosage
Chemical Substances	Isoflavones ; RGS Proteins ; Vitamin D (1406-16-2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2014-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639406-1
ISSN	1544-0737 ; 0895-9374
ISSN (online)	1544-0737
ISSN	0895-9374
DOI	10.1177/0022034514529305
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Article ; Online: In Vivo 3D Histomorphometry Quantifies Bone Apposition and Skeletal Progenitor Cell Differentiation.

Yeh, Shu-Chi A / Wilk, Katarzyna / Lin, Charles P / Intini, Giuseppe

Scientific reports

2018 Volume 8, Issue 1, Page(s) 5580

Abstract: Histomorphometry and Micro-CT are commonly used to assess bone remodeling and bone microarchitecture. These approaches typically require separate cohorts of animals to analyze 3D morphological changes and involve time-consuming immunohistochemistry ... ...

Abstract	Histomorphometry and Micro-CT are commonly used to assess bone remodeling and bone microarchitecture. These approaches typically require separate cohorts of animals to analyze 3D morphological changes and involve time-consuming immunohistochemistry preparation. Intravital Microscopy (IVM) in combination with mouse genetics may represent an attractive option to obtain bone architectural measurements while performing longitudinal monitoring of dynamic cellular processes in vivo. In this study we utilized two-photon, multicolor fluorescence IVM together with a lineage tracing reporter mouse model to image skeletal stem cells (SSCs) in their calvarial suture niche and analyze their differentiation fate after stimulation with an agonist of the canonical Wnt pathway (recombinant Wnt3a). Our in vivo histomorphometry analyses of bone formation, suture volume, and cellular dynamics showed that recombinant Wnt3a induces new bone formation, differentiation and incorporation of SSCs progeny into newly forming bone. IVM technology can therefore provide additional dynamic 3D information to the traditional static 2D histomorphometry.
MeSH term(s)	Animals ; Bone and Bones/cytology ; Cell Differentiation ; Imaging, Three-Dimensional ; Mice ; Microscopy, Fluorescence, Multiphoton ; Stem Cells/cytology
Language	English
Publishing date	2018-04-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-23785-6
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