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Fogel H, Yeritsyan D, Momenzadeh K, Kheir N, Yeung CM, Abbasian M, Lozano EM, Nazarian RM, Nazarian A. The effect of cannabinoids on single-level lumbar arthrodesis outcomes in a rat model. Spine J 2024; 24:1759-1772. [PMID: 38704096 DOI: 10.1016/j.spinee.2024.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 04/17/2024] [Accepted: 04/25/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND CONTEXT The opioid epidemic is a public health crisis affecting spine care and pain management. Medical marijuana is a potential nonopioid analgesic yet to be studied in the surgical setting since its effects on bone healing are not fully understood. Studies have demonstrated analgesic and potentially osteoinductive properties of cannabinoids with endocannabinoid receptor expression in bone tissue. PURPOSE We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion. STUDY DESIGN Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4-L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1 ml intraperitoneal injections weekly as follows: placebo (saline), 5 mg/kg THC, 5 mg/kg CBD, and a combination of 5 mg/kg THC and 5mg/kg CBD (Combo). METHODS Callus tissue was harvested 2- and 8-weeks postsurgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4-L5 arthrodesis on all rats. μCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed. RESULTS μCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at 2 weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (p>.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points. CONCLUSION This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at 2 weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases. CLINICAL SIGNIFICANCE CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the postoperative setting following spinal fusions.
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Affiliation(s)
- Harold Fogel
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
| | - Diana Yeritsyan
- Musculoskeletal Translational Innovation Initiative, Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215, USA
| | - Kaveh Momenzadeh
- Musculoskeletal Translational Innovation Initiative, Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215, USA
| | - Nadim Kheir
- Musculoskeletal Translational Innovation Initiative, Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215, USA
| | - Caleb M Yeung
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
| | - Mohammadreza Abbasian
- Musculoskeletal Translational Innovation Initiative, Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215, USA
| | - Edith Martinez Lozano
- Musculoskeletal Translational Innovation Initiative, Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215, USA
| | - Rosalynn M Nazarian
- The Pathology Service, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
| | - Ara Nazarian
- Musculoskeletal Translational Innovation Initiative, Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215, USA; Department of Orthopedic Surgery, Yerevan State Medical University, 2 Koryun Street, Yerevan, 0025, Armenia.
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Hu Z, Qin Z, Xie J, Qu Y, Yin L. Cannabidiol and its application in the treatment of oral diseases: therapeutic potentials, routes of administration and prospects. Biomed Pharmacother 2024; 176:116271. [PMID: 38788594 DOI: 10.1016/j.biopha.2024.116271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/27/2024] [Accepted: 02/07/2024] [Indexed: 05/26/2024] Open
Abstract
Cannabidiol (CBD), one of the most important active ingredients in cannabis, has been reported to have some pharmacological effects such as antibacterial and analgesic effects, and to have therapeutic potential in the treatment of oral diseases such as oral cancer, gingivitis and periodontal diseases. However, there is a lack of relevant systematic research and reviews. Therefore, based on the etiology and clinical symptoms of several common oral diseases, this paper focuses on the therapeutic potential of CBD in periodontal diseases, pulp diseases, oral mucosal diseases, oral cancer and temporomandibular joint diseases. The pharmacological effects of CBD and the distribution and function of its receptors in the oral cavity are also summarized. In order to provide reference for future research and further clinical application of CBD, we also summarize several possible routes of administration and corresponding characteristics. Finally, the challenges faced while applying CBD clinically and possible solutions are discussed, and we also look to the future.
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Affiliation(s)
- Zonghao Hu
- School/Hospital of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Zishun Qin
- School/Hospital of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Jinhong Xie
- School/Hospital of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Yue Qu
- School/Hospital of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Lihua Yin
- School/Hospital of Stomatology, Lanzhou University, Lanzhou 730000, China.
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David C, de Souza JF, Silva AF, Grazioli G, Barboza AS, Lund RG, Fajardo AR, Moraes RR. Cannabidiol-loaded microparticles embedded in a porous hydrogel matrix for biomedical applications. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2024; 35:14. [PMID: 38353746 PMCID: PMC10866797 DOI: 10.1007/s10856-023-06773-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 12/19/2023] [Indexed: 02/16/2024]
Abstract
In this study, poly (lactic-co-glycolic acid) (PLGA) microparticles loaded with cannabidiol (CBD) were synthesized (PLGA@CBD microparticles) and embedded up to 10 wt% in a chondroitin sulfate/polyvinyl alcohol hydrogel matrix. In vitro chemical, physical, and biological assays were carried out to validate the potential use of the modified hydrogels as biomaterials. The microparticles had spherical morphology and a narrow range of size distribution. CBD encapsulation efficiency was around 52%, loading was approximately 50%. Microparticle addition to the hydrogels caused minor changes in their morphology, FTIR and thermal analyses confirmed these changes. Swelling degree and total porosity were reduced in the presence of microparticles, but similar hydrophilic and degradation in phosphate buffer solution behaviors were observed by all hydrogels. Rupture force and maximum strain at rupture were higher in the modified hydrogels, whereas modulus of elasticity was similar across all materials. Viability of primary human dental pulp cells up to 21 days was generally not influenced by the addition of PLGA@CBD microparticles. The control hydrogel showed no antimicrobial activity against Staphylococcus aureus, whereas hydrogels with 5% and 10% PLGA@CBD microparticles showed inhibition zones. In conclusion, the PLGA@CBD microparticles were fabricated and successfully embedded in a hydrogel matrix. Despite the hydrophobic nature of CBD, the physicochemical and morphological properties were generally similar for the hydrogels with and without the CBD-loaded microparticles. The data reported in this study suggested that this original biomaterial loaded with CBD oil has characteristics that could enable it to be used as a scaffold for tissue/cellular regeneration.
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Affiliation(s)
- Carla David
- Biopathological Research Group, Faculty of Dentistry (GIBFO), University of the Andes, Mérida, Venezuela.
- Graduate Program in Dentistry, Universidade Federal de Pelotas, Pelotas, Brazil.
| | - Jaqueline F de Souza
- Laboratory of Technology and Development of Composites and Polymeric Materials-LaCoPol, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Adriana F Silva
- Graduate Program in Dentistry, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Guillermo Grazioli
- Department of Dental Materials, Universidad de la República, Montevideo, Uruguay
| | - Andressa S Barboza
- Graduate Program in Dentistry, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Rafael G Lund
- Graduate Program in Dentistry, Universidade Federal de Pelotas, Pelotas, Brazil
| | - André R Fajardo
- Laboratory of Technology and Development of Composites and Polymeric Materials-LaCoPol, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Rafael R Moraes
- Graduate Program in Dentistry, Universidade Federal de Pelotas, Pelotas, Brazil
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Kulpa J, Eglit G, Hill ML, MacNair L, Yardley H, Ware MA, Bonn-Miller MO, Peters EN. Serum Markers of Bone Turnover Following Controlled Administration of Two Medical Cannabis Products in Healthy Adults. Cannabis Cannabinoid Res 2024; 9:300-309. [PMID: 36346322 PMCID: PMC10874824 DOI: 10.1089/can.2022.0181] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Introduction: Cannabidiol (CBD) has been shown to maintain bone integrity in pre-clinical models, but little is known about the effects of delta-9-tetrahydrocannabinol (THC) on bone turnover. In this study we explored the effects of two oral medical cannabis products on normal bone homeostasis through evaluation of markers of bone resorption (carboxyl-terminal collagen crosslinks, CTx) and bone formation (procollagen type 1 N-terminal propeptide, P1NP; alkaline phosphatase, ALP). Methods: This study is an analysis of secondary data from two Phase 1 double-blind, placebo-controlled trials of Spectrum Yellow (0.9 mg THC, 20 mg CBD/mL of oil) and Spectrum Red (2.5 mg THC, 0.3 mg CBD/softgel). Healthy participants (n=38 men, 45 women) were randomized to receive 5-20 mg THC (CBD levels varied as a function of administered product) or placebo daily (BID) for 7 days. Bone markers were assessed at baseline, upon completion of product administration (day 8), and after a 5-day washout (day 13). Results: All bone markers were significantly higher in men at baseline (p≤0.008). For CTx, there was a significant day×group interaction (F=3.23, p=0.04); CTx levels were significantly lower in participants treated with Spectrum Red (b=-164.28; 95% confidence interval [CI], -328 to -0.29; p=0.04) and marginally lower in participants treated with Spectrum Yellow (b=-157.31; 95% CI, -323 to 8.68; p=0.06) versus placebo on day 8. For P1NP and ALP, there were no significant differences between treatments across study days. Bone marker values outside the reference range (RR) were observed; CTx > RR (n=71) was predominantly (85.9%) observed in male participants, whereas P1NP > RR (n=100) was more evenly distributed between sexes (53.0% in men). These were not considered clinically significant and did not differ between treatment groups. Conclusions: These are the first interventional human data on the effect of cannabinoids on biomarkers of bone turnover. Short-term treatment with CBD- or THC-dominant medical cannabis products resulted in attenuation of a marker of bone resorption. Although the attenuation was not clinically significant, this finding may be indicative of protective properties of cannabinoids in bone. Further research over longer dosing durations in individuals exhibiting bone-specific conditions (e.g., osteoporosis) is warranted. ClinicalTrials.gov IDs: ACTRN12619001723178 and ACTRN12619001450101.
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Affiliation(s)
| | | | - Melanie L. Hill
- School of Medicine, University of California, San Diego, La Jolla, California, USA
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Kumari P, Shirumalla RK, Bhalla V, Alam MS. New Emerging Aspect of Herbal Extracts for the Treatment of Osteoporosis: Overview. Curr Rheumatol Rev 2024; 20:361-372. [PMID: 38173067 DOI: 10.2174/0115733971273691231121131455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 01/05/2024]
Abstract
As the global population ages, osteoporosis is becoming a more common silent disease. Osteoporosis is characterized by decreased bone quality and strength, which increases the risk of fragility fractures in the elderly. According to estimates, 50% of women eventually suffer from an osteoporotic fracture. Due to increasing disability, more frequent hospital hospitalizations, and most critically, fragility fractures have been linked to a reduced quality of life. Osteoporotic fractures have been linked to an increased mortality risk; and must be considered in awareness as a serious health concern. There are anti-osteoporotic medications available that improve bone quality. Considering the availability of various treatment options, still there are a lot of underserved needs in the treatment of fractures and osteoporosis. For example, the application of natural products and herbal resources for fracture healing, because of the androgen-like and antioxidant characteristics of the plants, they can play a crucial for accelerating the repair of bone fractures. In this article, we'll discuss the herbal remedies that are essential for treating osteoporosis (bone disease).
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Affiliation(s)
- Priyanka Kumari
- Department of Pharmacology, SGT College of Pharmacy, SGT University, Gurgaon-Badli Road Chandu, Budhera, Gurugram, Haryana 122505, India
| | - Raj K Shirumalla
- Department of Pharmacology, SGT College of Pharmacy, SGT University, Gurgaon-Badli Road Chandu, Budhera, Gurugram, Haryana 122505, India
| | - Vijay Bhalla
- SGT College of Pharmacy, Department of Pharmacology, SGT University, Gurgaon-Badli Road Chandu, Budhera, Gurugram, Haryana 122505, India
| | - Md Sabir Alam
- Department of Pharmaceutics, SGT College of Pharmacy, Gurgaon-Badli Road Chandu, Budhera, Gurugram, Haryana 122505, India
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Montreekachon P, Chaichana N, Makeudom A, Kerdvongbundit V, Krisanaprakornkit W, Krisanaprakornkit S. Proliferative effect of cannabidiol in human gingival fibroblasts via the mitogen-activated extracellular signal-regulated kinase (MEK) 1/2. J Periodontal Res 2023; 58:1223-1234. [PMID: 37641169 DOI: 10.1111/jre.13178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 08/12/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND AND OBJECTIVES Cannabidiol exerts its anti-inflammatory and anti-oxidant activities in various human cells. However, its proliferative effect has not been extrapolated to human gingival fibroblasts (HGFs). This study aimed to determine the proliferative and promigratory effects of cannabidiol in HGFs and to elucidate the signaling mechanism(s). MATERIALS AND METHODS HGFs, characterized by their CD73, CD90, and CD105 expressions by flow cytometry, were treated with cannabidiol at 0.01-30 μM. The cytotoxicity was determined by the MTT assay, while the proliferative effect was examined by the BrdU assay, immunoblot and immunofluorescence for cyclin D1 and Ki-67 expressions, respectively, and cell cycle analysis. The promigratory effect of cannabidiol was investigated by a wound healing assay. Phosphorylation of the p38 MAPK, JNK, and ERK upon treatment with cannabidiol was explored, and their involvement in cell proliferation and cyclin D1 and Ki-67 expressions was studied using pharmacological inhibitors. RESULTS No toxicity was found in HGFs treated with any doses of cannabidiol up to 30 μM. The mean percentage of cell proliferation was significantly enhanced by treatment with cannabidiol at 3 or 10 μM (p < .001), consistent with upregulated expressions of cyclin D1 and Ki-67 and increased percentages of HGFs in the S and G2/M phases. Moreover, treatment with cannabidiol significantly induced cell migration (p < .05). The p38 MAPK and ERK1/2 were significantly activated by cannabidiol (p < .05), but only pretreatment with UO126, a MEK1/2 inhibitor, significantly inhibited cell proliferation and cyclin D1 and Ki-67 expressions (p < .05). CONCLUSION Treatment with cannabidiol at non-toxic doses promotes HGFs' proliferation and migration.
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Affiliation(s)
- Pattanin Montreekachon
- Department of Restorative Dentistry and Periodontology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Nopphanai Chaichana
- Department of Restorative Dentistry and Periodontology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Anupong Makeudom
- School of Dentistry, Mae Fah Luang University, Chiang Rai, Thailand
| | | | | | - Suttichai Krisanaprakornkit
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Oral and Maxillofacial Biology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
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Lu JJ, Shi XJ, Fu Q, Li YC, Zhu L, Lu N. MicroRNA-584-5p/RUNX family transcription factor 2 axis mediates hypoxia-induced osteogenic differentiation of periosteal stem cells. World J Stem Cells 2023; 15:979-988. [PMID: 37970237 PMCID: PMC10631372 DOI: 10.4252/wjsc.v15.i10.979] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/23/2023] [Accepted: 10/17/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND The hypoxic environment during bone healing is important in regulating the differentiation of periosteal stem cells (PSCs) into osteoblasts or chondrocytes; however, the underlying mechanisms remain unclear. AIM To determine the effect of hypoxia on PSCs, and the expression of microRNA-584-5p (miR-584-5p) and RUNX family transcription factor 2 (RUNX2) in PSCs was modulated to explore the impact of the miR-584-5p/RUNX2 axis on hypoxia-induced osteogenic differentiation of PSCs. METHODS In this study, we isolated primary mouse PSCs and stimulated them with hypoxia, and the characteristics and functional genes related to PSC osteogenic differentiation were assessed. Constructs expressing miR-584-5p and RUNX2 were established to determine PSC osteogenic differentiation. RESULTS Hypoxic stimulation induced PSC osteogenic differentiation and significantly increased calcified nodules, intracellular calcium ion levels, and alkaline phosphatase (ALP) activity in PSCs. Osteogenic differentiation-related factors such as RUNX2, bone morphogenetic protein 2, hypoxia-inducible factor 1-alpha, and ALP were upregulated; in contrast, miR-584-5p was downregulated in these cells. Furthermore, upregulation of miR-584-5p significantly inhibited RUNX2 expression and hypoxia-induced PSC osteogenic differentiation. RUNX2 was the target gene of miR-584-5p, antagonizing miR-584-5p inhibition in hypoxia-induced PSC osteogenic differentiation. CONCLUSION Our study showed that the interaction of miR-584-5p and RUNX2 could mediate PSC osteogenic differentiation induced by hypoxia.
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Affiliation(s)
- Jia-Jia Lu
- Department of Orthopedic Trauma Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200001, China
- Department of Orthopedic Trauma Surgery, Shanghai Changzheng Hospital, Shanghai 200001, China
| | - Xiao-Jian Shi
- Department of Orthopedic Trauma, Haimen People's Hospital of Jiangsu Province, Nantong 226100, Jiangsu Province, China
| | - Qiang Fu
- Department of Orthopedic Trauma Surgery, Shanghai Changzheng Hospital, Shanghai 200001, China
| | - Yong-Chuan Li
- Department of Orthopedic Trauma Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200001, China
| | - Lei Zhu
- Department of Orthopedic Trauma Surgery, Shanghai Changzheng Hospital, Shanghai 200001, China
| | - Nan Lu
- Department of Orthopedic Trauma Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200001, China.
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Deng M, Luo J, Cao H, Li Y, Chen L, Liu G. METTL14 represses osteoclast formation to ameliorate osteoporosis via enhancing GPX4 mRNA stability. ENVIRONMENTAL TOXICOLOGY 2023; 38:2057-2068. [PMID: 37195267 DOI: 10.1002/tox.23829] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/19/2023] [Accepted: 05/01/2023] [Indexed: 05/18/2023]
Abstract
Excessive bone resorption by osteoclasts results in the development of multiple bone disorders including osteoporosis. This study aimed to explore the biological function of methyltransferase-like14 (METTL14) in osteoclast formation, as well as its related mechanisms. Expression levels of METTL14, GPX4 and osteoclast-related proteins TRAP, NFATc1, c-Fos were detected by qRT-PCR and Western blotting. The osteoporosis model was established in mice by bilateral ovariectomy (OVX). Bone histomorphology was determined by micro-CT and H&E staining. NFATc1 expression in bone tissues was determined by immunohistochemical staining. Proliferation of primary bone marrow macrophages cells (BMMs) was assessed by MTT assay. Osteoclast formation was observed by TRAP staining. The regulatory mechanism was evaluated by RNA methylation quantification assay, MeRIP-qPCR, dual luciferase reporter assay, and RIP, respectively. METTL14 was down-regulated in the serum samples of postmenopausal osteoporotic women, which was positively associated with bone mineral density (BMD). Osteoclast formation was promoted in OVX-treated METTL14+/- mice as compared with wild-type littermates. Conversely, METTL14 overexpression repressed RANKL-induced osteoclast differentiation of BMMs. Mechanistically, METTL14-mediated m6A modification post-transcriptionally stabilized glutathione peroxidase 4 (GPX4), with the assistance of Hu-Antigen R (HuR). Finally, GPX4 depletion-mediated osteoclast formation in BMMs could be counteracted by METTL14 or HuR overexpression. Collectively, METTL14 inhibits osteoclastogenesis and bone resorption via enhancing GPX4 stability through an m6A-HuR dependent mechanism. Therefore, targeting METTL14 might be a novel promising treatment strategy for osteoporosis.
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Affiliation(s)
- Mingsi Deng
- Department of Stomatology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
- Department of Orthodontics, Changsha Stomatology Hospital, Changsha, Hunan, People's Republic of China
| | - Jia Luo
- Changsha Blood Center, Changsha, Hunan, People's Republic of China
| | - Heng Cao
- The Department of Wound Joint Surgery, Affiliated Hospital of Yiyang Medical College, Yiyang, Hunan, People's Republic of China
| | - Yong Li
- Department of Emergency, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Liangjian Chen
- Department of Stomatology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Gengyan Liu
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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Zheng J, He C, Jiang W, Liu S, Li F, Chi M, Cheng S, Liu Y. Screening for IBs-relative genes by transcriptome analysis and generation IBs-less mutants in Culter alburnus. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2023; 47:101106. [PMID: 37413699 DOI: 10.1016/j.cbd.2023.101106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 07/08/2023]
Abstract
Intermuscular bones (IBs), distributed specifically in the myosepta on both sides of lower teleosts, negatively affect palatability and processing. Recent research in zebrafish and several economically important farmed fishes has led to the breakthrough discovery of the mechanism of IBs formation and generation of IBs-loss mutants. This study explored the ossification patterns of IBs in juvenile Culter alburnus. Besides, some key genes and bone-related signaling pathways were identified by transcriptomic data. Furthermore, PCR microarray validation revealed that claudin1 could potentially regulate IBs formation. Additionally, we created several IBs-reduced mutants of C. alburnus by loss of the function of bone morphogenetic proteins 6 (bmp6) gene using CRISPR/Cas9 editing. These results suggested that CRISPR/Cas9-mediated bmp6 knockout was promising approach for breeding IBs-free strain in other cyprinids.
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Affiliation(s)
- Jianbo Zheng
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Changxi He
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Engineering Research Center of Aquaculture, National Demonstration Center for Experimental Fisheries Science Education, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Wenping Jiang
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Shili Liu
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Fei Li
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou, China.
| | - Meili Chi
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Shun Cheng
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Yinuo Liu
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
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Kulpa J, Harrison A, Rudolph L, Eglit GML, Turcotte C, Bonn-Miller MO, Peters EN. Oral Cannabidiol Treatment in Two Postmenopausal Women with Osteopenia: A Case Series. Cannabis Cannabinoid Res 2023; 8:S83-S89. [PMID: 37721991 DOI: 10.1089/can.2023.0060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2023] Open
Abstract
Introduction: Cannabidiol (CBD), a nonintoxicating cannabinoid, may be involved in bone remodeling, but human studies are limited. In this case series, we explored the effects of oral CBD administration on bone turnover. Materials and Methods: Two postmenopausal women with osteopenia (T-score=-1 to -2.5) were randomized to receive 100 or 300 mg CBD daily (oral, bis in die [twice per day]) for 12 weeks. Serum markers of bone resorption (carboxyl-terminal collagen crosslinks [CTx]) and bone formation (procollagen type 1 N-terminal propeptide [P1NP], bone-specific alkaline phosphatase [BSAP], and osteocalcin [OC]); safety measures; plasma concentrations of CBD and metabolites; sleep disturbance; symptoms of depression, anxiety, and stress; and quality of life, were assessed. Results: CBD was well tolerated, with no clinically significant change in vital signs, hematology, chemistry, or urinalysis, and no adverse events reported. Reductions (% change vs. baseline) in CTx (-8.5%, -28.1%), P1NP (-9.9%, -39.5%), BSAP (-12.7%, -74.8%), and OC (-16.0%, -6.7%) were observed after 12 weeks of oral administration of 100 or 300 mg CBD daily, respectively. The two participants self-reported consuming 95.3% and 98.8% of CBD doses, respectively. CBD and select metabolites were measurable in plasma after 4 and 12 weeks of CBD treatment. No notable changes in sleep disturbance, depression, anxiety, stress, or quality of life were observed. Conclusions: CBD was well tolerated after 12 weeks of twice-daily oral administration and was associated with reduction in measured markers of bone turnover. Compliance with CBD treatment was good. Large-scale randomized clinical trials into the bone protective effects of CBD in postmenopausal women are warranted.
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Affiliation(s)
- Justyna Kulpa
- Canopy Growth Corporation, Smiths Falls, Ontario, Canada
| | - Amy Harrison
- Canopy Growth Corporation, Smiths Falls, Ontario, Canada
| | - Lance Rudolph
- New Mexico Clinical Research and Osteoporosis Center, Albuquerque, New Mexico, USA
| | | | | | | | - Erica N Peters
- Canopy Growth Corporation, Smiths Falls, Ontario, Canada
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11
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Shikonin promotes rat periodontal bone defect repair and osteogenic differentiation of BMSCs by p38 MAPK pathway. Odontology 2022:10.1007/s10266-022-00774-w. [DOI: 10.1007/s10266-022-00774-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022]
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12
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Clouse G, Penman S, Hadjiargyrou M, Komatsu DE, Thanos PK. Examining the role of cannabinoids on osteoporosis: a review. Arch Osteoporos 2022; 17:146. [PMID: 36401719 DOI: 10.1007/s11657-022-01190-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 11/11/2022] [Indexed: 11/20/2022]
Abstract
PURPOSE Prior research studies have shown that the endocannabinoid system, influenced by CBD and THC, plays a role in bone remodeling. As both the research on cannabis and use of cannabis continue to grow, novel medicinal uses of both its constituents as well as the whole plant are being discovered. This review examines the role of cannabinoids on osteoporosis, more specifically, the endocannabinoid system and its role in bone remodeling and the involvement of the cannabinoid receptors 1 and 2 in bone health, as well as the effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and synthetic cannabinoids on bone. METHODS A comprehensive literature search of online databases including PUBMED was utilized. RESULTS A total of 29 studies investigating the effects of cannabis and/or its constituents as well as the activation or inactivation of cannabinoid receptors 1 and 2 were included and discussed. CONCLUSION While many of the mechanisms are still not yet fully understood, both preclinical and clinical studies show that the effects of cannabis mediated through the endocannabinoid system may prove to be an effective treatment option for individuals with osteoporosis.
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Affiliation(s)
- Grace Clouse
- Behavioral Neuropharmacology and Neuroimaging Laboratory On Addictions (BNNLA), Research Institute On Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14203, USA
| | - Samantha Penman
- Behavioral Neuropharmacology and Neuroimaging Laboratory On Addictions (BNNLA), Research Institute On Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14203, USA
| | - Michael Hadjiargyrou
- Department of Biological and Chemical Sciences, New York Institute of Technology, Old Westbury, NY, USA
| | - David E Komatsu
- Department of Orthopedics, Stony Brook University, Stony Brook, NY, USA
| | - Panayotis K Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory On Addictions (BNNLA), Research Institute On Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14203, USA. .,Department of Psychology, University at Buffalo, Buffalo, NY, 14203, USA.
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13
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Lin B, Xu P, Zheng J, Deng X, Ye Q, Huang Z, Wang N. Effects and mechanisms of natural alkaloids for prevention and treatment of osteoporosis. Front Pharmacol 2022; 13:1014173. [PMID: 36210805 PMCID: PMC9539536 DOI: 10.3389/fphar.2022.1014173] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 08/31/2022] [Indexed: 11/20/2022] Open
Abstract
Natural alkaloids are polycyclic, nitrogen-containing, and basic compounds obtained from plants. In this review, the advances in bioactive alkaloids with respect to their chemical structures, herbal sources, and effects for the prevention and treatment of osteoporosis are discussed. Anti-osteoporosis alkaloids are classified into six categories based on the chemical structure, namely, isoquinoline alkaloids, quinolizidine alkaloids, piperidine alkaloids, indole alkaloids, pyrrolizidine alkaloids and steroidal alkaloids. They promote mesenchymal stem cells differentiation, improve osteoblast proliferation, stimulate osteoblast autophagy and suppress osteoclast formation. These natural alkaloids can regulate multiple signaling pathways, including interrupting the tumor necrosis factor receptor associated factor 6- receptor activator of nuclear factor kappa B interaction, inhibiting the nuclear factor kappa B pathway in osteoclasts, activating the p38 mitogen-activated protein kinases pathway in osteoblasts, and triggering the wingless and int-1 pathway in mesenchymal stem cells. This review provides evidence and support for novel drug and clinical treatment of osteoporosis using natural alkaloids.
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Affiliation(s)
- Bingfeng Lin
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Pingcui Xu
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Juan Zheng
- Hangzhou Institute for Food and Drug Control, Hangzhou, China
| | - Xuehui Deng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qitao Ye
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhongping Huang
- College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, China
| | - Nani Wang
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
- *Correspondence: Nani Wang,
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14
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Bradley S, Young S, Bakke AM, Holcombe L, Waller D, Hunt A, Pinfold K, Watson P, Logan DW. Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs. Front Vet Sci 2022; 9:977457. [PMID: 36213402 PMCID: PMC9533147 DOI: 10.3389/fvets.2022.977457] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
Cannabidiol (CBD) containing dog food and treats are widely commercially available, mirroring the growing popularity of CBD as a supplement for humans. Despite this, experimental evidence of the safety and efficacy of long-term oral exposure in dogs is lacking. The purpose of this study was to address the gap in knowledge around the longer-term suitability and tolerance of a broad-spectrum CBD (THC-free) distillate in clinically healthy dogs. The study was a randomized, placebo-controlled, and blinded study where one group of twenty dogs received daily CBD capsules at a dose of 4 mg/kg of body weight (BW) for a period of 6 months. The control group of twenty dogs received placebo capsules. A comprehensive suite of physiological health measures was performed throughout the study at baseline, and after 2, 4, 10, 18, and 26 weeks of exposure, followed by 4 weeks of washout. CBD concentrations were measured at the same cadence in plasma, feces and urine. Health measures included biochemistry, hematology, urinalysis, in addition to fortnightly veterinary examinations, twice daily well-being observations, and a daily quality-of-life survey. Biochemistry and hematology showed no clinically significant alterations apart from a transient elevation in alkaline phosphatase (ALP) in just over half of the dogs receiving CBD. This elevation was observed in the absence of concurrent elevations of other liver parameters, and without any adverse effects on health and wellbeing. Furthermore, bone alkaline phosphatase (BALP) was simultaneously elevated with a significant, strong (r > 0.9) positive correlation between the two measures, suggesting that the elevation of total ALP was at least partly due to the bone-derived isoform. This study provides evidence that a once-daily oral dose of 4 mg CBD/kg BW is well tolerated in clinically healthy dogs for a duration of 6-months.
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15
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Valenti C, Billi M, Pancrazi GL, Calabria E, Armogida NG, Tortora G, Pagano S, Barnaba P, Marinucci L. Biological Effects of Cannabidiol on Human Cancer Cells: Systematic Review of the Literature. Pharmacol Res 2022; 181:106267. [DOI: 10.1016/j.phrs.2022.106267] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022]
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16
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Hydroxyapatite Use in Spine Surgery—Molecular and Clinical Aspect. MATERIALS 2022; 15:ma15082906. [PMID: 35454598 PMCID: PMC9030649 DOI: 10.3390/ma15082906] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 04/03/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022]
Abstract
Hydroxyapatite possesses desirable properties as a scaffold in tissue engineering: it is biocompatible at a site of implantation, and it is degradable to non-toxic products. Moreover, its porosity enables infiltration of cells, nutrients and waste products. The outcome of hydroxyapatite implantation highly depends on the extent of the host immune response. Authors emphasise major roles of the chemical, morphological and physical properties of the surface of biomaterial used. A number of techniques have been applied to transform the theoretical osteoconductive features of HAp into spinal fusion systems—from integration of HAp with autograft to synthetic intervertebral implants. The most popular uses of HAp in spine surgery include implants (ACDF), bone grafts in posterolateral lumbar fusion and transpedicular screws coating. In the past, autologous bone graft has been used as an intervertebral cage in ACDF. Due to the morbidity related to autograft harvesting from the iliac bone, a synthetic cage with osteoconductive material such as hydroxyapatite seems to be a good alternative. Regarding posterolateral lumbar fusion, it requires the graft to induce new bone growth and reinforce fusion between the vertebrae. Hydroxyapatite formulations have shown good results in that field. Moreover, the HAp coating has proven to be an efficient method of increasing screw fixation strength. It can decrease the risk of complications such as screw loosening after pedicle screw fixation in osteoporotic patients. The purpose of this literature review is to describe in vivo reaction to HAp implants and to summarise its current application in spine surgery.
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17
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Qi J, Zheng Z, Hu L, Wang H, Tang B, Lin L. Development and characterization of cannabidiol-loaded alginate copper hydrogel for repairing open bone defects in vitro. Colloids Surf B Biointerfaces 2022; 212:112339. [PMID: 35114435 DOI: 10.1016/j.colsurfb.2022.112339] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 01/12/2022] [Accepted: 01/12/2022] [Indexed: 02/04/2023]
Abstract
The clinical treatment of open bone defects caused by accidental bone trauma, bone tumors, bone diseases and bone infections is challenging. In this study, we designed and fabricated a multifunctional alginate-based hydrogel that contains cannabidiol (CBD), SA@Cu/CBD hydrogel, for repairing open bone defects. The results of physicochemical characterization showed that the SA@Cu/CBD hydrogel was successfully prepared and showed a suitable swelling ratio, high thermal stability, and stable mechanical properties. In vitro evaluation of antibacterial activity indicated that more than 90% of S. aureus and E. coli were inhibited compared to the control group. The ALP activity assay showed that the ALP expression level of MC3T3-E1cells in SA@Cu/CBD hydrogel was approximately 2-fold higher than that in the control group on day 7 and 14. Additionally, compared to the control group, the level of mineralized deposits in SA@Cu/CBD hydrogel was also improved by about 2 times on day 14. The PCR results indicated the mRNA expression levels of osteogenic markers (ALP, Col1α1, OCN, and RUNX2 genes) and angiogenic markers (EGFL6 and VEGF genes) in SA@Cu/CBD hydrogel were significantly upregulated compared to that in the control group, and the mRNA expression levels of critical inflammatory cytokines (TNF-α and IL-1β) in the SA@Cu/CBD hydrogel were significantly down-regulated compared to that in SA@Cu hydrogel. Taken together, these results demonstrated that the SA@Cu/CBD hydrogel showed significantly anti-bacterial, anti-inflammation, angiogenic and osteogenic activities in vitro studies. Thus, SA@Cu/CBD hydrogels may be a promising candidate in repairing open bone defects.
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Affiliation(s)
- Jianchao Qi
- Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China; Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, PR China; Department of Emergency surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, PR China; Shenzhen Key Laboratory of Cell Microenvironment, PR China
| | - Zhe Zheng
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, PR China
| | - Liqiu Hu
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, PR China
| | - Huizhen Wang
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, PR China; Shenzhen Key Laboratory of Cell Microenvironment, PR China
| | - Bin Tang
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, PR China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, PR China; Shenzhen Key Laboratory of Cell Microenvironment, PR China.
| | - Lijun Lin
- Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
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18
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Song L, Zhou R, Xiao J, He L, Zhu F, Li C, Dai F. Demineralized bone matrix combined with cytotoxic T-lymphocyte-associated protein 4 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells and suppresses the activation of T lymphocytes in vitro. J Tissue Eng Regen Med 2021; 16:290-296. [PMID: 34965018 DOI: 10.1002/term.3281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 11/11/2022]
Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) can promote osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMMSCs), and CTLA4-modified bone marrow mesenchymal stem cells possess immunoregulatory effects. In the present study, we aimed to construct a new tissue engineering bone using demineralized bone matrix and CTLA4 protein, designated as DBM-CTLA4 (+). The effects of DBM-CTLA4 (+) on the osteogenic differentiation of hBMMSCs and T lymphocyte activation were evaluated through in vitro experiments. The cumulative release of CTLA4 from DBM-CTLA4 (+) was determined using enzyme-linked immunosorbent assay. DBM-CTLA4 (+) was co-cultured in a Transwell chamber with either phytohemagglutinin-treated hBMMSCs or human peripheral blood mononuclear cells (hPBMCs). Osteogenic differentiation of hBMMSCs was assessed by calcium deposition, ALP activity, and the protein levels of COL1A1, RUNX2, BMP2, and OPN. T lymphocyte activity was assessed by measuring the protein levels of IL-2, L-17, HLA-DRA1, IFN-γ, and RANKL. Our results showed that the cumulative release rates of CTLA4 at 7, 14, 21, and 28 days were 12.6% ± 1.4%, 30.2% ± 2.3%, 49.8% ± 3.8%, and 60.5% ± 2.7%, respectively. Compared to the negative control, DBM-CTLA4 (+) promoted the proliferation of hBMMSCs, and enhanced calcium deposition, ALP activity, and protein levels of COL1A1, RUNX2, BMP2, and OPN. Moreover, DBM-CTLA4 (+) decreased the levels of IL-2, IL-17, HLA-DR, IFN-γ, and RANKL in hPBMCs treated with phytohemagglutinin. In conclusion, DBM-CTLA4 (+) promoted proliferation and osteogenic differentiation of hBMMSCs and suppressed T lymphocyte activation.
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Affiliation(s)
- Lei Song
- Department of Orthopedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Rui Zhou
- Department of Orthopedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Jun Xiao
- Department of Orthopedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Lei He
- Department of Orthopedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Fang Zhu
- Department of Orthopedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Congcan Li
- Department of Orthopedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Fei Dai
- Department of Orthopedics, First Affiliated Hospital, Army Medical University, Chongqing, China
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