Administration of tauroursodeoxycholic acid enhances osteogenic differentiation of bone marrow-derived mesenchymal stem cells and bone regeneration

Cha, Byung-Hyun,Jung, Moon-Joo,Moon, Bo-Kyung,Kim, Jin-Su,Ma, Yoonji,Arai, Yoshie,Noh, Myungkyung,Shin, Jung-Youn,Kim, Byung-Soo,Lee, Soo-Hong Elsevier 2016 Bone Vol.83 No.-

<P><B>Abstract</B></P> <P>It is known that osteogenic differentiation of mesenchymal stem cells (MSCs) can be promoted by suppression of adipogenesis of MSCs. We have recently found that the chemical chaperone tauroursodeoxycholic acid (TUDCA) significantly reduces adipogenesis of MSCs. In the present study, we examined whether TUDCA can promote osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) by regulating Integrin 5 (ITGA5) associated with activation of ERK1/2 signal pathway and thereby enhance bone tissue regeneration by reducing apoptosis and the inflammatory response. TUDCA treatment promoted <I>in vitro</I> osteogenic differentiation of BMMSCs and <I>in vivo</I> bone tissue regeneration in a calvarial defect model, as confirmed by micro-computed tomography, histological staining, and immunohistochemistry for osteocalcin. In addition, TUDCA treatment significantly decreased apoptosis and the inflammatory response <I>in vivo</I> and <I>in vitro</I>, which is important to enhance bone tissue regeneration. These results indicate that TUDCA plays a critical role in enhancing osteogenesis of BMMSCs, and is therefore a potential alternative drug for bone tissue regeneration.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Tauroursodeoxycholic acid (TUDCA) promotes osteogenic differentiation of mouse bone marrow mesenchymal stem cells (mBMMSCs). </LI> <LI> TUDCA stimulates Integrin 5 (ITGA5) associated with activation of ERK1/2 signal pathway. </LI> <LI> TUDCA enhances bone tissue regeneration by the suppression of apoptosis and inflammatory response. </LI> <LI> TUDCA promotes bone tissue regeneration in mouse calvarial defects. </LI> <LI> Ursodeoxycholic acid (UDCA), which has a similar chemical structure to TUDCA, also increases bone regeneration. </LI> <LI> TUDCA is a useful pharmacological substitute for BMP-2, which is clinically available for bone tissue regeneration. </LI> </UL> </P>

Synergistic Effect of Bone Marrow-Derived Mesenchymal Stem Cells and Platelet-Rich Plasma on Bone Regeneration of Calvarial Defects in Rabbits

오남식,윤정호,유재흥,최성호,이명현,이상진,송순욱 한국조직공학과 재생의학회 2012 조직공학과 재생의학 Vol.9 No.1

Bone tissue regeneration techniques include tissue engineering approaches which employ mesenchymal stem cells as an osteogenic agent for bone repair. Recent studies have demonstrated that tissue engineering scaffolds and growth factors can support cell proliferation, bone formation, and bone tissue repair in lost bone tissue. Furthermore,many studies have suggested that platelet-rich plasma (PRP) can improve bone regeneration due to the numerous growth factors that it contains. This study was performed to investigate the influence of bone marrow-derived mesenchymal stem cells (BMMSCs) and PRP on bone regeneration of calvarial defects in rabbits. Hydroxyapatite (HA) was used as a scaffold for bone regeneration. There were three groups in this experiment: 1) HA loaded with BMMSCs (HS group), 2) HA loaded with PRP (HP group), and 3) HA loaded with BMMSCs and PRP (HSP group). Bone tissue regeneration techniques include tissue engineering approaches which employ mesenchymal stem cells as an osteogenic agent for bone repair. Recent studies have demonstrated that tissue engineering scaffolds and growth factors can support cell proliferation, bone formation, and bone tissue repair in lost bone tissue. Furthermore,many studies have suggested that platelet-rich plasma (PRP) can improve bone regeneration due to the numerous growth factors that it contains. This study was performed to investigate the influence of bone marrow-derived mesenchymal stem cells (BMMSCs) and PRP on bone regeneration of calvarial defects in rabbits. Hydroxyapatite (HA) was used as a scaffold for bone regeneration. There were three groups in this experiment: 1) HA loaded with BMMSCs (HS group), 2) HA loaded with PRP (HP group), and 3) HA loaded with BMMSCs and PRP (HSP group). Two circular bony defects (6 mm in diameter) were made in rabbit calvaria using a trephine bur. BMMSCs and PRP with a HA scaffold (diameter 5.5 mm, height 3 mm) were applied to each defect. The animals were sacrificed after 2 weeks, 4 weeks and 8 weeks. The level of their ability of osteogenesis was evaluated through histological and histomorphometric analyses. High-quality bone regeneration was observed in the HSP group. The percentage of new bone area around the scaffolds was higher in the HSP group than it was in the other groups (HS and HP group), especially at 8 weeks (HS, 72.5±15 %; HP, 85.8±14 %; HSP, 98.8±2.5%). In addition, the level of bone maturation was higher in the HSP group than in the other groups. The results of this study show that PRP has a positive effect on bone generation. HA with a combination of BMMSCs and PRP can enhance bone regeneration. In addition, the growth factor capacity of PRP may affect the differentiation of BMMSCs and promote bone formation.

차폐막을 이용한 치주조직 및 골조직 유도재생술의 실패요인에 대한 고찰

염혜리,구영,정종평,Yeom, Hey-Ri,Ku, Young,Chung, Chong-Pyoung 대한치주과학회 1997 Journal of Periodontal & Implant Science Vol.27 No.1

Using barrier membrane, guided bone regeneration(GBR) and guided tissue regeneration(GTR) of periodontal tissue are now widely studied and good results were reported. In bone regeneration, not all cases gained good results and in some cases using GTR, bone were less regenerated than that of control. The purpose of this study is to search for the method to improve the success rate of GBR and GTR by examination of the cause of the failure. For these study, rats and beagle dogs were used. In rat study, 5mm diameter round hole was made on parietal bone of the rat and 10mm diameter of bioresorbable membrane was placed on the bone defects and sutured. In 1 ,2, 4 weeks later, the rats were sacrificed and Masson-Trichrome staining was done and inspected under light microscope for guided bone regeneration. In dog study, $3{\times}4mm^2$ Grade III furcation defect was made at the 3rd and 1th premolar on mandible of 6 beagle dogs. The defects were covered by bioresorbable membrane extending 2-3mm from the defect margin. The membrane was sutured and buccal flap was covered the defect perfectly. In 2, 4. 8 weeks later. the animals were sacrificed and undecalcified specimens were made and stained by multiple staining method. In rats. there was much amount of new bone formation at 2 weeks. and in 4 weeks specimen, bony defect was perfectly dosed and plenty amount of new bone marrow was developed. In some cases, there were failures of guided bone regeneration. In beagle dogs, guided tissue regeneration was incomplete when the defect was collapsed by the membrane itself and when the rate of resorption was so rapid than expected. The cause of the failure in GBR and GTR procedure is that 1) the membrane was not tightly seal the bony defects. If the sealing was not perfect, fibrous connective tissue infiltrate into the defect and inhibit the new bone formation and regeneration. 2) the membrane was too tightly attached to the tissue and then there was no space to be regenerated. In conclusion, the requirements of the membrane for periodontal tissue and bone regeneration are the biocompatibility, degree of sealingness, malleability. space making and manipulation. In this animal study. space making for new bone and periodontal ligament, and sealing the space might be the most important point for successful accomplishment of GBR and GTR.

Biomineralization of bone tissue: calcium phosphate-based inorganics in collagen fibrillar organic matrices

Min-Ho Hong,Jung Heon Lee,Hyun Suk Jung,신흥수,Hyunjung Shin 한국생체재료학회 2022 생체재료학회지 Vol.26 No.3

Background: Bone regeneration research is currently ongoing in the scientific community. Materials approved for clinical use, and applied to patients, have been developed and produced. However, rather than directly affecting bone regeneration, these materials support bone induction, which regenerates bone. Therefore, the research community is still researching bone tissue regeneration. In the papers published so far, it is hard to find an improvement in the theory of bone regeneration. This review discusses the relationship between the existing theories on hard tissue growth and regeneration and the biomaterials developed so far for this purpose and future research directions. Mainbody: Highly complex nucleation and crystallization in hard tissue involves the coordinated action of ions and/or molecules that can produce different organic and inorganic composite biomaterials. In addition, the healing of bone defects is also affected by the dynamic conditions of ions and nutrients in the bone regeneration process. Inorganics in the human body, especially calcium- and/or phosphorus-based materials, play an important role in hard tissues. Inorganic crystal growth is important for treating or remodeling the bone matrix. Biomaterials used in bone tissue regeneration require expertise in various fields of the scientific community. Chemical knowledge is indispensable for interpreting the relationship between biological factors and their formation. In addition, sources of energy for the nucleation and crystallization processes of such chemical bonds and minerals that make up the bone tissue must be considered. However, the exact mechanism for this process has not yet been elucidated. Therefore, a convergence of broader scientific fields such as chemistry, materials, and biology is urgently needed to induce a distinct bone tissue regeneration mechanism. Conclusion: This review provides an overview of calcium- and/or phosphorus-based inorganic properties and processes combined with organics that can be regarded as matrices of these minerals, namely collagen molecules and collagen fibrils. Furthermore, we discuss how this strategy can be applied to future bone tissue regenerative medicine in combination with other academic perspectives.

Bioactive calcium phosphate materials and applications in bone regeneration

정지운,Jung Hun Kim,심정희,Nathaniel S. Hwang,허찬영 한국생체재료학회 2019 생체재료학회지 Vol.23 No.1

Background: Bone regeneration involves various complex biological processes. Many experiments have been performed using biomaterials in vivo and in vitro to promote and understand bone regeneration. Among the many biomaterials, calcium phosphates which exist in the natural bone have been conducted a number of studies because of its bone regenerative property. It can be directly contributed to bone regeneration process or assist in the use of other biomaterials. Therefore, it is widely used in many applications and has been continuously studied. Mainbody: Calcium phosphate has been widely used in bone regeneration applications because it shows osteoconductive and in some cases osteoinductive features. The release of calcium and phosphorus ions regulates the activation of osteoblasts and osteoclasts to facilitate bone regeneration. The control of surface properties and porosity of calcium phosphate affects cell/protein adhesion and growth and regulates bone mineral formation. Properties affecting bioactivity vary depending on the types of calcium phosphates such as HAP, TCP and can be utilized in various applications because of differences in ion release, solubility, stability, and mechanical strength. In order to make use of these properties, different calcium phosphates have been used together or mixed with other materials to complement their disadvantages and to highlight their advantages. Calcium phosphate has been utilized to improve bone regeneration in ways such as increasing osteoconductivity for bone ingrowth, enhancing osteoinductivity for bone mineralization with ion release control, and encapsulating drugs or growth factors. Conclusion: Calcium phosphate has been used for bone regeneration in various forms such as coating, cement and scaffold based on its unique bioactive properties and bone regeneration effectiveness. Additionally, several studies have been actively carried out to improve the efficacy of calcium phosphate in combination with various healing agents. By summarizing the properties of calcium phosphate and its research direction, we hope that calcium phosphate can contribute to the clinical treatment approach for bone defect and disease.

줄기세포 기반의 치주조직재생

박재욱,박주철 대한구강해부학회 2014 대한구강해부학회지 Vol.35 No.1

Periodontium is complex tissue composed of cementum, periodontal ligament and alveolar bone which holds the tooth in the bone. periodontitis is main cause of tooth loss leads to loss of attachment of connective tissue and irreversible bony destruction. So periodontitis has been one of the main concern to dentist, patient and oral health system. For recent years the main purpose of periodontics is regeneration of damaged peroidontium on shape, structure and function. In periodontal regeneration, new connective tissue fibers should be inserted in the cementum and bone, and construct the complex cementum-ligament-bone interfaces and provide a functional connection between a tooth and the surrounding jaw. Recently, many surgical, nonsurgical therapies and bone substitutes are using, but the clinical outcomes are still limiting. Bone transplantation or bone substitutes like guided bone regeneration, guided tissue regeneration don't have the capacity to regenerate destructed connective tissue. With cell based therapy, numerous growth factors and modulating agents have used but it made limited success. Stem cell based therapy is the most active researching field in medical and dental area. However, when diseased periodontal condition, tissue repair does not occur naturally because of the lack of sound stem cells. So exogenous regenerative tools such as ex vivo expanded/ manipulated stem cells will be needed to replenish the host cell niche and facililtate tissue regeneration. As the increasing success of regenerating other tissues(skin, cartilage, bone, cardiovascular component, pancreas), stem cell based periodontal regeneration with tissue engineering approach can be new field of treatment. Comparing stem cells from other sites of adult body, dental stem cells have advantage that is easy access to gaining site and have characteristics like proliferation, differentiation, and flexiblity. Some kind of reviewed stem cells, dental pulp stem cells (DPSCs), Stem cells from exfoliated deciduous teeth (SHED), PDL stem cells (PDLSCs), Stem cells from apical papilla, apical papilla stem cells (SCAP), Dental follicle cells (DFCs), and MSCs are most actively studied for stem cell based periodontal regeneration. However, safety problems are not completely examined, and the difficulty of ex vivo proliferation is still recognized to limiatation of stem cells. With effective stem cell delivery strategy, research to overcome these limitations should be continued. With recent advancement of stem cell based periodontal tissue engineering and periodontal regeneration, next step of research should be concentrated to clinical application of this advanced therapeutic method. Accordingly, further studies are required to develop new methods to identify and maintain multipotent stem cells in vitro and to determine the long term safety and efficacy of ex vivo expanded stem cells to repair periodontal defects in large animal models. With partial regeneration of tooth, whole tooth regeneration has been actively studied. When whole tooth regeneration succeed, regenerating periodontal ligament and contact of tooth-periodontium are needed to transplant regenerated tooth. So periodontal regeneration is essential step to achieve whole tooth regeneration and replantation.

Stepwise verification of bone regeneration using recombinant human bone morphogenetic protein-2 in rat fibula model

Jung Woo Nam,Hyung Jun Kim 대한구강악안면외과학회 2017 대한구강악안면외과학회지 Vol.43 No.6

Objectives: The purpose of this study was to introduce our three experiments on bone morphogenetic protein (BMP) and its carriers performed using the critical sized segmental defect (CSD) model in rat fibula and to investigate development of animal models and carriers for more effective bone regeneration. Materials and Methods: For the experiments, 14, 16, and 24 rats with CSDs on both fibulae were used in Experiments 1, 2, and 3, respectively. BMP-2 with absorbable collagen sponge (ACS) (Experiments 1 and 2), autoclaved autogenous bone (AAB) and fibrin glue (FG) (Experiment 3), and xenogenic bone (Experiment 2) were used in the experimental groups. Radiographic and histomorphological evaluations were performed during the follow-up period of each experiment. Results: Significant new bone formation was commonly observed in all experimental groups using BMP-2 compared to control and xenograft (porcine bone) groups. Although there was some difference based on BMP carrier, regenerated bone volume was typically reduced by remodeling after initially forming excessive bone. Conclusion: BMP-2 demonstrates excellent ability for bone regeneration because of its osteoinductivity, but efficacy can be significantly different depending on its delivery system. ACS and FG showed relatively good bone regeneration capacity, satisfying the essential conditions of localization and release-control when used as BMP carriers. AAB could not provide release-control as a BMP carrier, but its space-maintenance role was remarkable. Carriers and scaffolds that can provide sufficient support to the BMP/carrier complex are necessary for large bone defects, and AAB is thought to be able to act as an effective scaffold. The CSD model of rat fibula is simple and useful for initial estimate of bone regeneration by agents including BMPs.

각종 골대체물질들의 골형성능에 관한 비교연구

설정현,최원희,김정철,홍정수,서동보 大韓成形外科學會 1992 Archives of Plastic Surgery Vol.19 No.4

We studied the bone forming capacity of the various bone substitute materials for the confirmation of bone regeneration with each case i.e Hydroxyapatite(SURGIBON), kiel obne, B.O.P. and bone dust. The bone dust was used for control. In 18 New Zealand white rabbits, four partial thickness bone defects were created on the outer table of parietal bone, which were measured 1.5mm in depth x 8mm in diameter. Bone substitute materials were filled in each bone defect. The animals were sacrified at 2, 4, 6, 8 weeks after taking a plain skull film, and then both macroscopic and microscopic examinations were done. The results were as follows : 1. Hydroxyapatite : good bone regeneration with moderately increased eosinophil. 2. KIEL BONE : no bone regeneration and markedly increased eosinophil. 3. B.O.P. : no evidence of bone growth during postoperative 8 weeks. 4. BONE DUST : persistent osteoblast existed during experimental period, more likely as own bone. We summarized that the hydroxyapatite is a biocompatible matrix implantable as a bone graft substitute and more bone regeneration than other bone substitutes during the experimental period.

Neurovascular Interaction and Exercise Training for Bone Regeneration

이승용 한국운동생리학회 2023 운동과학 Vol.32 No.2

The nervous and vascular systems are widely distributed in the skeletal system and play an important role in bone metabolism and bone formation, respectively. Their independent impact on the skeletal system has received keen attention in bone-related research over the decade. However, the mechanism of neurovascular coupling during physiological bone remodeling and regeneration has recently been highlighted, considering the importance of spatial relationships between bone-associated skeletal nerves and blood vessels. In addition, the positive effect of exercise on the bones has been continuously emphasized, as evident by the improved number and function of skeletal nerves and blood vessels following exercise training. Skeletal nerve-vascular crosstalk and exercise training are essential for bone development and regeneration, respectively; however, the effect of exercise on neurovascular interactions has not yet been studied. This review aims to summarize the regulatory roles of the nerves and blood vessels in bone metabolism and regeneration and to highlight a combination of potential cellular processes of neurogenesis and angiogenesis in bone regeneration. Moreover, given the significance of the spatial relationship between nerves and blood vessels in bones and the role of exercise training, this review aims to discuss the potential physiological neurovascular coupling that occurs following exercise and physical activity.

The Effect of Carrier for BMP-2 Delivery on Histological Aspects of Tissue-Engineered Bone

정선영,고유진,장현석,강선웅,박정호 한국조직공학과 재생의학회 2013 조직공학과 재생의학 Vol.10 No.6

Bone morphogenetic protein-2 (BMP-2) that can regenerate bone by recruiting osteo-progenitor cells and inducing osteogenic differentiation has been highlighted as an alternative therapy to treat bone defects. The thera-peutic effect of BMP-2 depends considerably on the delivery carriers. Previous studies demonstrated that collagen and fibrin have the potential to serve as a carrier for delivery of BMP-2. The successful bone regeneration by col-lagen and fibrin with BMP-2 implantation has been shown in animal models. However, those studies were not focused on the effect of the carriers on the quality of the regenerated bone. In this study, we directly compared the quality of regenerated bone when BMP-2 was delivered with collagen or fibrin, both of which are shown to be excel-lent carrier for BMP-2. The microstructure, surface morphology, BMP-2 release profile was examined in vitro. To evaluate the quality of regenerated bone, both types of BMP-2 carriers were implanted into the dorsal subcutaneous spaces of the mice. Four and six weeks after implantation, the regenerated bone was evaluated by computed tomog-raphy, histology, and histomorphometric analysis. The bone regeneration by the collagen with BMP-2 was higher bone density than bone regenerated by the fibrin with BMP-2. The results of this study show that carrier of BMP-2is an important factor affecting the quality of engineered bone.