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Jha SS, Jeyaraman N, Jeyaraman M, Ramasubramanian S, Muthu S, Santos GS, da Fonseca LF, Lana JF. Cross-talks between osteoporosis and gut microbiome. World J Orthop 2025; 16:102274. [PMID: 40124724 PMCID: PMC11924030 DOI: 10.5312/wjo.v16.i3.102274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 01/06/2025] [Accepted: 02/06/2025] [Indexed: 03/12/2025] Open
Abstract
The gut microbiome comprises a vast community of microbes inhabiting the human alimentary canal, playing a crucial role in various physiological functions. These microbes generally live in harmony with the host; however, when dysbiosis occurs, it can contribute to the pathogenesis of diseases, including osteoporosis. Osteoporosis, a systemic skeletal disease characterized by reduced bone mass and increased fracture risk, has attracted significant research attention concerning the role of gut microbes in its development. Advances in molecular biology have highlighted the influence of gut microbiota on osteoporosis through mechanisms involving immunoregulation, modulation of the gut-brain axis, and regulation of the intestinal barrier and nutrient absorption. These microbes can enhance bone mass by inhibiting osteoclast differentiation, inducing apoptosis, reducing bone resorption, and promoting osteoblast proliferation and maturation. Despite these promising findings, the therapeutic effectiveness of targeting gut microbes in osteoporosis requires further investigation. Notably, gut microbiota has been increasingly studied for their potential in early diagnosis, intervention, and as an adjunct therapy for osteoporosis, suggesting a growing utility in improving bone health. Further research is essential to fully elucidate the therapeutic potential and clinical application of gut microbiome modulation in the management of osteoporosis.
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Affiliation(s)
- Shiva Shankar Jha
- Department of Orthopaedics, Harishchandra Orthopaedic Research Institute, Patna 880023, Bihar, India
| | - Naveen Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
| | - Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
| | - Swaminathan Ramasubramanian
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
| | - Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Karur 639004, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Biotechnology, Faculty of Engineering, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India
| | - Gabriel Silva Santos
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
| | - Lucas Furtado da Fonseca
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
| | - José Fábio Lana
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, São Paulo, Brazil
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Melis S, Trompet D, Chagin AS, Maes C. Skeletal stem and progenitor cells in bone physiology, ageing and disease. Nat Rev Endocrinol 2025; 21:135-153. [PMID: 39379711 DOI: 10.1038/s41574-024-01039-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/30/2024] [Indexed: 10/10/2024]
Abstract
Skeletal stem cells (SSCs) and related progenitors with osteogenic potential, collectively termed skeletal stem and/or progenitor cells (SSPCs), are crucial for providing osteoblasts for bone formation during homeostatic tissue turnover and fracture repair. Besides mediating normal bone physiology, they also have important roles in various metabolic bone diseases, including osteoporosis. SSPCs are of tremendous interest because they represent prime future targets for osteoanabolic therapies and bone regenerative medicine. Remarkable progress has been made in characterizing various SSC and SSPC populations in postnatal bone. SSPCs exist in the periosteum and within the bone marrow stroma, including subsets localizing around arteriolar and sinusoidal blood vessels; they can display osteogenic, chondrogenic, adipogenic and/or fibroblastic potential, and exert critical haematopoiesis-supportive functions. However, much remains to be clarified. By the current markers, bona fide SSCs are commonly contained within broader SSPC populations characterized by considerable heterogeneity and overlap, whose common versus specific functions in health and disease have not been fully unravelled. Here, we review the present knowledge of the identity, fates and relationships of SSPC populations in the postnatal bone environment, their contributions to bone maintenance, the changes observed upon ageing, and the effect of metabolic diseases such as osteoporosis and diabetes mellitus.
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Affiliation(s)
- Seppe Melis
- Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Dana Trompet
- Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Andrei S Chagin
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Christa Maes
- Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
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Kang TH, Chung ST, Seo IW, Cho M, Lee JH. Bone turnover markers are risk factors for endplate injuries during lumbar interbody fusion: a retrospective case-control study. J Orthop Surg Res 2025; 20:192. [PMID: 39987433 PMCID: PMC11847339 DOI: 10.1186/s13018-025-05585-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 02/06/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Intraoperative endplate injury (IEI) is a type of fracture and a potential complication during lumbar interbody fusion (LIF). Osteoporosis diagnosed by bone mineral density (BMD) is a well-known risk factor for fracture itself and IEI also. The bone turnover markers (BTMs) are parameters of bone qualities and have some correlations with fractures, but there is no study about the BTMs and intraoperative fractures especially IEI. This study aims to identify the correlation between IEI and BTMs, especially in misTLIF. METHODS We retrospectively reviewed 184 patients (230 spine levels). The IEI was diagnosed as the breakage of the endplate observed on postoperative 1 mm thin-cut CT scans. All surgical and endogenous risk factors of IEI were also checked including the bone resorption marker (serum CTX) and bone formation marker (serum P1NP) of BTMs. Additionally, the ratio (P1NP/CTX) and the subtype groups of BTMs were analyzed. RESULTS The rate of total IEI was 38%. The sex, osteoporosis, spine BMD, femur BMD, CTX, P1NP/CTX, preoperative disc height, and the discrepancy between preoperative disc height and cage size were risk factors in multivariate logistic regression analyses. The subtypes according to BTMs showed a different rate of IEI, resulting in subtype 2 A (low CTX and P1NP and high P1NP/CTX ratio) having the lowest incidence and statistically significant odds ratios compared to other subtype groups. CONCLUSION This study demonstrated that the IEI is related to BTMs regardless of BMD in misTLIF. In addition, the P1NP/CTX ratio or subtypes could be helpful in predicting the risk of IEI due to the parallel dynamics of BTMs.
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Affiliation(s)
- Tae Hoon Kang
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, 20, Boramae-ro 5-gil, Seoul, South Korea
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Sung Taek Chung
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, 20, Boramae-ro 5-gil, Seoul, South Korea
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - In-Wook Seo
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, 20, Boramae-ro 5-gil, Seoul, South Korea
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Minjoon Cho
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, 20, Boramae-ro 5-gil, Seoul, South Korea
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Jae Hyup Lee
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, 20, Boramae-ro 5-gil, Seoul, South Korea.
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, Republic of Korea.
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4
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Indrio F, Salatto A. Gut Microbiota-Bone Axis. ANNALS OF NUTRITION & METABOLISM 2025:1-10. [PMID: 39848230 DOI: 10.1159/000541999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/11/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Knowledge of the complex interplay between gut microbiota and human health is gradually increasing as it has just recently been a field of such great interest. SUMMARY Recent studies have reported that communities of microorganisms inhabiting the gut influence the immune system through cellular responses and shape many physiological and pathophysiological aspects of the body, including muscle and bone metabolism (formation and resorption). Specifically, the gut microbiota affects skeletal homeostasis through changes in host metabolism, the immune system, hormone secretion, and the gut-brain axis. The major role on gut-bone axis is due to short-chain fatty acids (SCFAs). They have the ability to influence regulatory T-cell (Tregs) development and activate bone metabolism through the action of Wnt10. SCFA production may be a mechanism by which the microbial community, by increasing the serum level of insulin-like growth factor 1 (IGF-1), leads to the growth and regulation of bone homeostasis. A specific SCFA, butyrate, diffuses into the bone marrow where it expands Tregs. The Tregs induce production of the Wnt ligand Wnt10b by CD8+ T cells, leading to activation of Wnt signaling and stimulation of bone formation. At the hormonal level, the effect of the gut microbiota on bone homeostasis is expressed through the biphasic action of serotonin. Some microbiota, such as spore-forming microbes, regulate the level of serotonin in the gut, serum, and feces. Another group of bacterial species (Lactococcus, Mucispirillum, Lactobacillus, and Bifidobacterium) can increase the level of peripheral/vascular leptin, which in turn manages bone homeostasis through the action of brain serotonin.
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Affiliation(s)
- Flavia Indrio
- Department of Experimental Medicine, University of Salento, Lecce, Italy
| | - Alessia Salatto
- Department of Translational Medical Science, University of Naples Federico II, Napoli, Italy
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5
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Wang LY, Liang LM, Zhang XX, Chi H, Peng FL. Short bouts and long-term exercise reduce sedentary-induced bone loss and microstructural changes by modulating bone formation and resorption in healthy young male rats. Sci Rep 2025; 15:1825. [PMID: 39805876 PMCID: PMC11730605 DOI: 10.1038/s41598-024-82243-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 12/03/2024] [Indexed: 01/16/2025] Open
Abstract
Although the toxic effect of Sedentary behavior (SED) on bone health has been demonstrated in the previous study, the underlying mechanisms of SED, or break SED to bone health remain unclear. In this study, we aim to investigate the effects of sedentary behavior (SED) on bone health, as well as the potential favor effects of moderate to vigorous physical activity (MVPA) and periodic interruptions of SED. To simulate SED, we used small Plexiglas cages (20.0 × 9.0 × 10.0 cm) to restrict animal movement. Short bursts of exercise to break SED and continuous long-term exercise were also designed. After an 8-weeks period of SED, we observed decreased bone mass and bone microstructure. Specifically, there was a notable decrease in the bone mineral density (BMD), bone surface (BS) and cortical thickness (Ct.Th) significantly reduced in cortical bone. In the trabecular bone, parameters such as trabecular separation (Tb.Sp), trabecular number (Tb.N), BS, connectivity density (Conn.D), BS/BV, bone volume/tissue volume (BV/TV), degree of anisotropy (DA), and structural model index (SMI) were also significantly reduced. In addition, we detected an increase in serum tartrate-resistant acid phosphatase (TRAP) levels in SED rats at both 4 and 8 weeks. At 8 weeks, the osteoclast number and surface with TRAP-staining were significantly increased, however, the OPG mRNA and proteins level were significantly decreased. After daily short bouts exercise and long-term exercise, we observed improvements in bone mass and microstructure. These improvements included increasing BMD and BV/TV of cortical bone, and improving Conn.D, BV/TV, DA and SMI of trabecular. Meanwhile, we found that, at 4 and 8 weeks, there was an increase in serum ALP. At 8 weeks, the mineralized nodules surface with Alizarin Red S-staining, and OPG mRNA and proteins level in bone tissue were significantly increased. Our findings suggest that SED leads to alterations in the bone mass and microstructure, which are associated with the changes in the OPG protein and bone remodeling. Exercise, whether in short daily bouts or continuous long-term sessions, can ameliorate the harmful effects of SED. Similarly, the changes in bone mass and microstructure from exercise are also associated with the changes in the OPG protein and bone remodeling by upregulated osteoblast activity to bone formation. Overall, our findings indicate the importance of physical activity in maintaining bone health and preventing the negative impacts of prolonged SED.
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Affiliation(s)
- L Y Wang
- Guangxi Normal University, Guangxi, China
- Guangxi Medical University, Guangxi, China
| | - L M Liang
- Guangxi Normal University, Guangxi, China.
| | - X X Zhang
- Guangxi Normal University, Guangxi, China
| | - H Chi
- Guangxi Normal University, Guangxi, China
| | - F L Peng
- Guangxi Normal University, Guangxi, China.
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Yamashita Y, Hayashi M, Liu A, Sasaki F, Tsuchiya Y, Takayanagi H, Saito M, Nakashima T. Fam102a translocates Runx2 and Rbpjl to facilitate Osterix expression and bone formation. Nat Commun 2025; 16:9. [PMID: 39747056 PMCID: PMC11695619 DOI: 10.1038/s41467-024-55451-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 12/11/2024] [Indexed: 01/04/2025] Open
Abstract
Bone remodeling maintains the robustness of the bone tissue by balancing bone resorption by osteoclasts and bone formation by osteoblasts. Although these cells together play a crucial role in bone remodeling, only a few reports are available on the common factors involved in the differentiation of the two types of cells. Here, we show family with sequence similarity 102 member A (Fam102a) as a bone-remodeling factor that positively regulates both osteoclast and osteoblast differentiation. Fam102a regulates osteoblast differentiation by controlling recombination signal binding protein for immunoglobulin κ J region-like (Rbpjl). The Fam102a-Rbpjl axis promotes the nuclear translocation of transcription factors and enhances the expression of Osterix, a transcription factor essential for osteoblast differentiation. The deletion of Fam102a or a functional mutation in Rbpjl leads to osteopenia accompanied by reduced osteoblastic bone formation. Thus, the Fam102a-Rbpjl axis plays an important role in osteoblasts and this finding provides insights into bone remodeling.
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Affiliation(s)
- Yu Yamashita
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Mikihito Hayashi
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
| | - Anhao Liu
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Fumiyuki Sasaki
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Yosuke Tsuchiya
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Hiroshi Takayanagi
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo, Japan
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Ramalho D, Rocha GM, Oliveira MJ. The Portuguese state of the art on osteoporosis and fracture risk: an
update on the treatment options. AKTUEL RHEUMATOL 2024; 49:385-394. [DOI: 10.1055/a-2158-0872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
AbstractOsteoporosis and fragility fractures are serious public health problems, which
greatly impact individual health and the economy of other health services.
Pharmacological treatment is still one of the main elements of clinical
intervention, combined with non-pharmacological measures, in preventing the
occurrence of fragility fractures. The emergence of promising new
pharmacological options in the treatment of osteoporosis seems to renew
expectations in the prevention of complications and a subsequent reduction in
morbidity and mortality, including symptomatic treatment, improved physical
function and a better quality of life. This review aims to provide updated
information on the pharmacological treatment of osteoporosis in the adult
population. A comprehensive PubMed search was performed to review the current
evidence on osteoporosis treatment. Of the 378 articles identified from the
initial queries, the final review included 80 articles. Currently, the following
pharmacological options are available: antiresorptive (bisphosphonates,
denosumab, postmenopausal hormone replacement therapy and selective oestrogen
receptor modulators), bone-forming agents (essentially, teriparatide and
abaloparatide) and the new dual-action therapy (romosozumab), recently approved
by the US Food and Drug Administration and the European Medicines Agency, but
which is not yet an option in Portugal. Therapeutic selection is essentially
based on assessment of cost-effectiveness, since current evidence does not
suggest any differences between the distinctive classes in reducing the risk of
fractures, but this analysis is limited by the scarcity of comparative
intraclass studies. Notwithstanding, romosozumab, as a dual effect therapy, is
promising in resolving the physiological limitations resulting from the merely
unilateral action of antiresorptive agents and bone-forming agents in the
inseparable relationship between bone formation and resorption. However, its
cardiovascular safety raises some concerns, and this topic is still being
debated. The underdiagnosis and the undertreatment of osteoporosis remain one of
the greatest challenges of the 21st century. Over the years, new drugs have
appeared that have tried to address these problems with a direct impact on the
health of populations, but a long way remains to be come in optimising their
effectiveness, safety and tolerability.
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Affiliation(s)
- Diogo Ramalho
- Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila
Nova de Gaia, Portugal
| | - Gustavo Melo Rocha
- Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila
Nova de Gaia, Portugal
| | - Maria João Oliveira
- Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila
Nova de Gaia, Portugal
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8
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Yan Q, Liu H, Zhu R, Zhang Z. Contribution of macrophage polarization in bone metabolism: A literature review. Cytokine 2024; 184:156768. [PMID: 39340960 DOI: 10.1016/j.cyto.2024.156768] [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: 08/06/2024] [Revised: 09/11/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024]
Abstract
Macrophage polarization divides macrophages into two main cell subpopulations, classically and alternatively activated macrophages (M1 and M2, respectively). M1 polarization promotes osteoclastogenesis, while M2 polarization promotes osteogenesis. The physiological homeostasis of bone metabolism involves a high dynamic balance between osteoclastic-mediated bone resorption and formation. Reportedly, M1/M2 imbalance causes the onset and persistence of inflammation-related bone diseases. Therefore, understanding the research advances in functions and roles of macrophages in such diseases will provide substantial guidance for improved treatment of bone diseases. In this review, we underscore and summarize the research advances in macrophage polarization, and bone-related diseases, such as rheumatoid arthritis, osteoarthritis, and osteoporosis, over the last 5 years. Our findings showed that targeting macrophages and balancing macrophage polarization can effectively reduce inflammation and decrease bone destruction while promoting bone formation and vascular repair. These results indicate that regulating macrophage and macrophage polarization to restore homeostasis is a prospective approach for curing bone-related diseases.
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Affiliation(s)
- Qiqi Yan
- Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Haixia Liu
- Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Ruyuan Zhu
- Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Zhiguo Zhang
- Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China.
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9
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Zaimi M, Grapsa E. Current therapeutic approach of chronic kidney disease-mineral and bone disorder. Ther Apher Dial 2024; 28:671-689. [PMID: 38898685 DOI: 10.1111/1744-9987.14177] [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: 02/29/2024] [Revised: 05/14/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024]
Abstract
Chronic kidney disease (CKD) has emerged as one of the leading noncommunicable diseases affecting >10% of the population worldwide. Bone and mineral disorders are a common complication among patients with CKD resulting in a poor life quality, high fracture risk, increased morbidity and cardiovascular mortality. According to Kidney Disease: Improving Global Outcomes, renal osteodystrophy refers to changes in bone morphology found in bone biopsy, whereas CKD-mineral and bone disorder (CKD-MBD) defines a complex of disturbances including biochemical and hormonal alterations, disorders of bone and mineral metabolism and extraskeletal calcification. As a result, the management of CKD-MBD should focus on the aforementioned parameters, including the treatment of hyperphosphatemia, hypocalcemia, abnormal PTH and vitamin D levels. Regarding the bone fragility fractures, osteoporosis and renal osteodystrophy, which constitute the bone component of CKD-MBD, anti-osteoporotic agents constitute the mainstay of treatment. However, a thorough elucidation of the CKD-MBD pathogenesis is crucial for the ideal personalized treatment approach. In this paper, we review the pathology and management of CKD-MBD based on the current literature with special attention to recent advances.
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Affiliation(s)
- Maria Zaimi
- National and Kapodistrian University of Athens, Aretaieio Hospital, Athens, Greece
| | - Eirini Grapsa
- National and Kapodistrian University of Athens, Aretaieio Hospital, Athens, Greece
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10
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Ramchand SK. Skeletal effects of adjuvant zoledronic acid and its cessation in women with early-stage breast cancer. J Bone Miner Res 2024; 39:1203-1204. [PMID: 39078001 DOI: 10.1093/jbmr/zjae120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/05/2024] [Accepted: 07/19/2024] [Indexed: 07/31/2024]
Affiliation(s)
- Sabashini K Ramchand
- Endocrinology and Metabolism Institute, Cleveland Clinic, Lerner College of Medicine - Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Medicine, Austin Health, The University of Melbourne, 145 Studley Road, Melbourne, Victoria 3084, Australia
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11
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Győri DS. Research on Bone Cells in Health and Disease. Int J Mol Sci 2024; 25:8758. [PMID: 39201445 PMCID: PMC11354530 DOI: 10.3390/ijms25168758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 08/09/2024] [Indexed: 09/02/2024] Open
Abstract
Bone-forming osteoblasts, osteocytes, and bone-resorbing osteoclasts are responsible for life-long skeletal remodeling [...].
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Affiliation(s)
- Dávid S Győri
- Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary
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12
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Kuah AH, Sattgast LH, Grant KA, Gonzales SW, Khadka R, Damrath JG, Allen MR, Burr DB, Wallace JM, Maddalozzo GF, Benton ML, Beaver LM, Branscum AJ, Turner RT, Iwaniec UT. Six months of voluntary alcohol consumption in male cynomolgus macaques reduces intracortical bone porosity without altering mineralization or mechanical properties. Bone 2024; 185:117111. [PMID: 38679220 PMCID: PMC466935 DOI: 10.1016/j.bone.2024.117111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 05/01/2024]
Abstract
Chronic heavy alcohol consumption is a risk factor for low trauma bone fracture. Using a non-human primate model of voluntary alcohol consumption, we investigated the effects of 6 months of ethanol intake on cortical bone in cynomolgus macaques (Macaca fascicularis). Young adult (6.4 ± 0.1 years old, mean ± SE) male cynomolgus macaques (n = 17) were subjected to a 4-month graded ethanol induction period, followed by voluntary self-administration of water or ethanol (4 % w/v) for 22 h/d, 7 d/wk. for 6 months. Control animals (n = 6) consumed an isocaloric maltose-dextrin solution. Tibial response was evaluated using densitometry, microcomputed tomography, histomorphometry, biomechanical testing, and Raman spectroscopy. Global bone response was evaluated using biochemical markers of bone turnover. Monkeys in the ethanol group consumed an average of 2.3 ± 0.2 g/kg/d ethanol resulting in a blood ethanol concentration of 90 ± 12 mg/dl in longitudinal samples taken 7 h after the daily session began. Ethanol consumption had no effect on tibia length, mass, density, mechanical properties, or mineralization (p > 0.642). However, compared to controls, ethanol intake resulted in a dose-dependent reduction in intracortical bone porosity (Spearman rank correlation = -0.770; p < 0.0001) and compared to baseline, a strong tendency (p = 0.058) for lower plasma CTX, a biochemical marker of global bone resorption. These findings are important because suppressed cortical bone remodeling can result in a decrease in bone quality. In conclusion, intracortical bone porosity was reduced to subnormal values 6 months following initiation of voluntary ethanol consumption but other measures of tibia architecture, mineralization, or mechanics were not altered.
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Affiliation(s)
- Amida H Kuah
- Skeletal Biology Laboratory, School of Nutrition and Public Health, Oregon State University, Corvallis, OR 97331, USA
| | - Lara H Sattgast
- Skeletal Biology Laboratory, School of Nutrition and Public Health, Oregon State University, Corvallis, OR 97331, USA
| | - Kathleen A Grant
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Steven W Gonzales
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Rupak Khadka
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - John G Damrath
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Matthew R Allen
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - David B Burr
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Joseph M Wallace
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Gianni F Maddalozzo
- Skeletal Biology Laboratory, School of Nutrition and Public Health, Oregon State University, Corvallis, OR 97331, USA
| | | | - Laura M Beaver
- Skeletal Biology Laboratory, School of Nutrition and Public Health, Oregon State University, Corvallis, OR 97331, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
| | - Adam J Branscum
- Biostatistics Program, School of Nutrition and Public Health, Oregon State University, Corvallis, OR 97331, USA
| | - Russell T Turner
- Skeletal Biology Laboratory, School of Nutrition and Public Health, Oregon State University, Corvallis, OR 97331, USA; Center for Healthy Aging Research, Oregon State University, Corvallis, OR 97331, USA
| | - Urszula T Iwaniec
- Skeletal Biology Laboratory, School of Nutrition and Public Health, Oregon State University, Corvallis, OR 97331, USA; Center for Healthy Aging Research, Oregon State University, Corvallis, OR 97331, USA.
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13
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Williams JA, Campsie P, Gibson R, Johnson-Love O, Werner A, Sprott M, Meechan R, Huesa C, Windmill JFC, Purcell M, Coupaud S, Dalby MJ, Childs P, Riddell JS, Reid S. Developing and Investigating a Nanovibration Intervention for the Prevention/Reversal of Bone Loss Following Spinal Cord Injury. ACS NANO 2024; 18:17630-17641. [PMID: 38924391 PMCID: PMC11238619 DOI: 10.1021/acsnano.4c02104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024]
Abstract
Osteoporosis disrupts the fine-tuned balance between bone formation and resorption, leading to reductions in bone quantity and quality and ultimately increasing fracture risk. Prevention and treatment of osteoporotic fractures is essential for reductions in mortality, morbidity, and the economic burden, particularly considering the aging global population. Extreme bone loss that mimics time-accelerated osteoporosis develops in the paralyzed limbs following complete spinal cord injury (SCI). In vitro nanoscale vibration (1 kHz, 30 or 90 nm amplitude) has been shown to drive differentiation of mesenchymal stem cells toward osteoblast-like phenotypes, enhancing osteogenesis and inhibiting osteoclastogenesis simultaneously. Here, we develop and characterize a wearable device designed to deliver and monitor continuous nanoamplitude vibration to the hindlimb long bones of rats with complete SCI. We investigate whether a clinically feasible dose of nanovibration (two 2 h/day, 5 days/week for 6 weeks) is effective at reversing the established SCI-induced osteoporosis. Laser interferometry and finite element analysis confirmed transmission of nanovibration into the bone, and microcomputed tomography and serum bone formation and resorption markers assessed effectiveness. The intervention did not reverse SCI-induced osteoporosis. However, serum analysis indicated an elevated concentration of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) in rats receiving 40 nm amplitude nanovibration, suggesting increased synthesis of type 1 collagen, the major organic component of bone. Therefore, enhanced doses of nanovibrational stimulus may yet prove beneficial in attenuating/reversing osteoporosis, particularly in less severe forms of osteoporosis.
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Affiliation(s)
- Jonathan A. Williams
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
- School
of Psychology and Neuroscience, College of Medical, Veterinary and
Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
- Scottish
Centre for Innovation in Spinal Cord Injury, Queen Elizabeth National
Spinal Injuries Unit, Queen Elizabeth University
Hospital, Glasgow G51 4TF, U.K.
| | - Paul Campsie
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
| | - Richard Gibson
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
| | - Olivia Johnson-Love
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
| | - Anna Werner
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
| | - Mark Sprott
- Centre
for the Cellular Microenvironment, Institute of Molecular, Cell and
Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
| | - Ryan Meechan
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
| | - Carmen Huesa
- Institute
of Infection, Immunity and Inflammation, College of Medical, Veterinary
and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
| | - James F. C. Windmill
- Department
of Electronic and Electrical Engineering, Royal College Building, University of Strathclyde, Glasgow G1 1XW, U.K.
| | - Mariel Purcell
- Scottish
Centre for Innovation in Spinal Cord Injury, Queen Elizabeth National
Spinal Injuries Unit, Queen Elizabeth University
Hospital, Glasgow G51 4TF, U.K.
| | - Sylvie Coupaud
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
- Scottish
Centre for Innovation in Spinal Cord Injury, Queen Elizabeth National
Spinal Injuries Unit, Queen Elizabeth University
Hospital, Glasgow G51 4TF, U.K.
| | - Matthew J. Dalby
- Centre
for the Cellular Microenvironment, Institute of Molecular, Cell and
Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
| | - Peter Childs
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
| | - John S. Riddell
- School
of Psychology and Neuroscience, College of Medical, Veterinary and
Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
| | - Stuart Reid
- Centre
for the Cellular Microenvironment, Department of Biomedical Engineering,
Wolfson Centre, University of Strathclyde, Glasgow G4 0NW, U.K.
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14
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Ramchand SK, Ghasem-Zadeh A, Hoermann R, White S, Yeo B, Francis PA, Xu CLH, Coleman O, Shore-Lorenti C, Ebeling PR, Zajac JD, Seeman E, Grossmann M. Denosumab Prevents Bone Loss and Microarchitectural Deterioration in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression Therapy: A Randomized Controlled Trial. J Clin Oncol 2024:JCO2302309. [PMID: 38954783 DOI: 10.1200/jco.23.02309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 03/03/2024] [Accepted: 04/09/2024] [Indexed: 07/04/2024] Open
Abstract
PURPOSE Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women. METHODS In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437). RESULTS Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted. CONCLUSION Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.
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Affiliation(s)
- Sabashini K Ramchand
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ali Ghasem-Zadeh
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
- Department of Endocrinology, Austin Health, University of Melbourne, Parkville, Australia
| | - Rudolf Hoermann
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
| | - Shane White
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
- Olivia Newton-John Cancer & Wellness Centre, Austin Health, Melbourne, Australia
| | - Belinda Yeo
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
- Olivia Newton-John Cancer & Wellness Centre, Austin Health, Melbourne, Australia
| | - Prudence A Francis
- Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia
| | - Cecilia L H Xu
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
| | - Olivia Coleman
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
| | - Cat Shore-Lorenti
- Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia
| | - Peter R Ebeling
- Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia
| | - Jeffrey D Zajac
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
- Department of Endocrinology, Austin Health, University of Melbourne, Parkville, Australia
| | - Ego Seeman
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
- Department of Endocrinology, Austin Health, University of Melbourne, Parkville, Australia
| | - Mathis Grossmann
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Australia
- Department of Endocrinology, Austin Health, University of Melbourne, Parkville, Australia
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15
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Gao Y, Huang A, Zhao Y, Du Y. PMAIP1 regulates autophagy in osteoblasts via the AMPK/mTOR pathway in osteoporosis. Hum Cell 2024; 37:1024-1038. [PMID: 38691334 DOI: 10.1007/s13577-024-01067-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/22/2024] [Indexed: 05/03/2024]
Abstract
Osteoporosis (OP) is a highly prevalent disorder characterized by low bone mass that severely reduces patient quality of life. Although numerous treatments for OP have been introduced in clinic, many have side effects and high costs. Therefore, there is still an unmet need for optimal solutions. Here, raw signal analysis was used to identify potential high-risk factors for OP, and the biological functions and possible mechanisms of action (MOAs) of these factors were explored via gene set enrichment analysis (GSEA). Subsequently, molecular biological experiments were performed to verify and analyze the discovered risk factors in vitro and in vivo. PMAIP1 was identified as a potential risk factor for OP and significantly suppressed autophagy in osteoblasts via the AMPK/mTOR pathway, thereby inhibiting the proliferation and differentiation of osteoblasts. Furthermore, we constructed an ovariectomy (OVX) model of OP in rats and simultaneously applied si-PMAIP1 for in vivo interference. si-PMAIP1 upregulated the expression of LC3B and p-AMPK and downregulated the expression of p-mTOR, and these effects were reversed by the autophagy inhibitor. Micro-CT revealed that, si-PMAIP1 significantly inhibited the development of osteoporosis in OVX model rats, and this therapeutic effect was attenuated by treatment with an autophagy inhibitor. This study explored the role and mechanism of PMAIP1 in OP and demonstrated that PMAIP1 may serve as a novel target for OP treatment.
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Affiliation(s)
- Yijie Gao
- Department of Rehabilitation Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China
- Dalian Medical University, Dalian, Liaoning, People's Republic of China
| | - Anquan Huang
- Department of Joint Surgery, Dalian Municipal Central Hospital, Dalian, Liaoning, People's Republic of China
| | - Yantao Zhao
- Department of Joint Surgery, Dalian Municipal Central Hospital, Dalian, Liaoning, People's Republic of China.
| | - Yunxia Du
- Department of Rehabilitation Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.
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16
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Lin W, Hu S, Li K, Shi Y, Pan C, Xu Z, Li D, Wang H, Li B, Chen H. Breaking Osteoclast-Acid Vicious Cycle to Rescue Osteoporosis via an Acid Responsive Organic Framework-Based Neutralizing and Gene Editing Platform. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2307595. [PMID: 38126648 DOI: 10.1002/smll.202307595] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/14/2023] [Indexed: 12/23/2023]
Abstract
In the osteoporotic microenvironment, the acidic microenvironment generated by excessive osteoclasts not only causes irreversible bone mineral dissolution, but also promotes reactive oxygen species (ROS) production to induce osteoblast senescence and excessive receptor activator of nuclear factor kappa-B ligand (RANKL) production, which help to generate more osteoclasts. Hence, targeting the acidic microenvironment and RANKL production may break this vicious cycle to rescue osteoporosis. To achieve this, an acid-responsive and neutralizing system with high in vivo gene editing capacity is developed by loading sodium bicarbonate (NaHCO3) and RANKL-CRISPR/Cas9 (RC) plasmid in a metal-organic framework. This results showed ZIF8-NaHCO3@Cas9 (ZNC) effective neutralized acidic microenvironment and inhibited ROS production . Surprisingly, nanoparticles loaded with NaHCO3 and plasmids show higher transfection efficiency in the acidic environments as compared to the ones loaded with plasmid only. Finally, micro-CT proves complete reversal of bone volume in ovariectomized mice after ZNC injection into the bone remodeling site. Overall, the newly developed nanoparticles show strong effect in neutralizing the acidic microenvironment to achieve bone protection through promoting osteogenesis and inhibiting osteolysis in a bidirectional manner. This study provides new insights into the treatment of osteoporosis for biomedical and clinical therapies.
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Affiliation(s)
- Wenzheng Lin
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
- Department of Orthopedics, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, P. R. China
- Jiangsu Key laboratory of integrated traditional Chinese and Western Medicine for prevention and treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, P. R. China
| | - Sihan Hu
- Orthopedic Institute, Department of Orthopedic Surgery, First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, 215006, P. R. China
| | - Ke Li
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
- Department of Orthopedics, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, P. R. China
| | - Yu Shi
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
- Department of Orthopedics, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, P. R. China
| | - Chun Pan
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
| | - Zhuobin Xu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
| | - Dandan Li
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
| | - Huihui Wang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
- Jiangsu Key laboratory of integrated traditional Chinese and Western Medicine for prevention and treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, P. R. China
| | - Bin Li
- Orthopedic Institute, Department of Orthopedic Surgery, First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, 215006, P. R. China
| | - Hao Chen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
- Department of Orthopedics, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, P. R. China
- Jiangsu Key laboratory of integrated traditional Chinese and Western Medicine for prevention and treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, P. R. China
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17
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Zhang Y, Li X, Lang J, Li W, Huang D, Sun W, Yang L, Li W, Wang Y, Zhang L. Basic-helix-loop-helix family member e41 suppresses osteoclastogenesis and abnormal bone resorption disease via NFATc1. iScience 2024; 27:109059. [PMID: 38375236 PMCID: PMC10875115 DOI: 10.1016/j.isci.2024.109059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 12/19/2023] [Accepted: 01/25/2024] [Indexed: 02/21/2024] Open
Abstract
Overactivation of osteoclasts due to altered osteoclastogenesis causes multiple bone metabolic diseases. However, how osteoclast differentiation is tightly regulated and involved in multiple pathophysiological states remains mystery. In this study, we noticed that the downregulation of BHLHE41 (basic-helix-loop-helix family member e41) was tightly associated with osteoclast differentiation and osteoporosis. Functionally, the upregulation or downregulation of BHLHE41 suppressed or promoted osteoclast differentiation, respectively, in vitro. A mechanism study indicated that the direct binding of BHLHE41 to the promoter region of NFATc1 that led to its downregulation. Notably, the inhibition of NFATc1 abrogated the enhanced osteoclast differentiation in BHLHE41-knockdown bone marrow macrophages (BMMs). Additionally, upregulation of BHLHE41 impeded bone destruction in OVX mice with osteoporosis. Therefore, our research reveals the mechanism by which BHLHE41 regulates osteoclast differentiation and bone resorption via NFATc1, and targeting BHLHE41 is a potential strategy for the treatment of osteoporosis.
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Affiliation(s)
- Yufeng Zhang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Xiaoguang Li
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Jianlong Lang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Wenbo Li
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Dengke Huang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Weizong Sun
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Li Yang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Wenhui Li
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yi Wang
- Department of Pain Management, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Liang Zhang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
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18
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Martin BL, Reynolds KJ, Fazzalari NL, Bottema MJ. Modelling the Effects of Growth and Remodelling on the Density and Structure of Cancellous Bone. Bull Math Biol 2024; 86:37. [PMID: 38436708 PMCID: PMC10912124 DOI: 10.1007/s11538-024-01267-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 02/08/2024] [Indexed: 03/05/2024]
Abstract
A two-stage model is proposed for investigating remodelling characteristics in bone over time and distance to the growth plate. The first stage comprises a partial differential equation (PDE) for bone density as a function of time and distance from the growth plate. This stage clarifies the contributions to changes in bone density due to remodelling and growth processes and tracks the rate at which new bone emanates from the growth plate. The second stage consists of simulating the remodelling process to determine remodelling characteristics. Implementing the second stage requires the rate at which bone moves away from the growth plate computed during the first stage. The second stage is also needed to confirm that remodelling characteristics predicted by the first stage may be explained by a realistic model for remodelling and to compute activation frequency. The model is demonstrated on microCT scans of tibia of juvenile female rats in three experimental groups: sham-operated control, oestrogen deprived, and oestrogen deprived followed by treatment. Model predictions for changes in bone density and remodelling characteristics agree with the literature. In addition, the model provides new insight into the role of treatment on the density of new bone emanating from the growth plate and provides quantitative descriptions of changes in remodelling characteristics beyond what has been possible to ascertain by experimentation alone.
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Affiliation(s)
- Brianna L Martin
- Marine Spatial Ecology Laboratory, School of the Environment, The University of Queensland, Level 5, Goddard Building, St. Lucia, QLD, 4072, Australia
| | - Karen J Reynolds
- Medical Device Research Institute, College of Science and Engineering, Flinders University, Tonsley Campus, 1284 South Rd, Clovelly Park, SA, 5042, Australia
| | - Nicola L Fazzalari
- Medical Device Research Institute, College of Science and Engineering, Flinders University, Tonsley Campus, 1284 South Rd, Clovelly Park, SA, 5042, Australia
| | - Murk J Bottema
- Medical Device Research Institute, College of Science and Engineering, Flinders University, Tonsley Campus, 1284 South Rd, Clovelly Park, SA, 5042, Australia.
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19
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Takegahara N, Kim H, Choi Y. Unraveling the intricacies of osteoclast differentiation and maturation: insight into novel therapeutic strategies for bone-destructive diseases. Exp Mol Med 2024; 56:264-272. [PMID: 38297158 PMCID: PMC10907717 DOI: 10.1038/s12276-024-01157-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/20/2023] [Accepted: 11/07/2023] [Indexed: 02/02/2024] Open
Abstract
Osteoclasts are the principal cells that efficiently resorb bone. Numerous studies have attempted to reveal the molecular pathways leading to the differentiation and activation of osteoclasts to improve the treatment and prevention of osteoporosis and other bone-destructive diseases. While the cumulative knowledge of osteoclast regulatory molecules, such as receptor activator of nuclear factor-kB ligand (RANKL) and nuclear factor of activated T cells 1 (NFATc1), contributes to the understanding of the developmental progression of osteoclasts, little is known about how the discrete steps of osteoclastogenesis modify osteoclast status but not the absolute number of osteoclasts. The regulatory mechanisms involved in osteoclast maturation but not those involved in differentiation deserve special attention due to their potential use in establishing a more effective treatment strategy: targeting late-phase differentiation while preserving coupled bone formation. Recent studies have shed light on the molecules that govern late-phase osteoclast differentiation and maturation, as well as the metabolic changes needed to adapt to shifting metabolic demands. This review outlines the current understanding of the regulation of osteoclast differentiation, as well as osteoclast metabolic adaptation as a differentiation control mechanism. Additionally, this review introduces molecules that regulate the late-phase osteoclast differentiation and thus minimally impact coupled bone formation.
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Affiliation(s)
- Noriko Takegahara
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Hyunsoo Kim
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Yongwon Choi
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
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20
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Muniyasamy R, Manjubala I. Insights into the Mechanism of Osteoporosis and the Available Treatment Options. Curr Pharm Biotechnol 2024; 25:1538-1551. [PMID: 37936474 DOI: 10.2174/0113892010273783231027073117] [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: 08/08/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 11/09/2023]
Abstract
Osteoporosis, one of the most prevalent bone illnesses, majorly affects postmenopausal women and men over 50 years of age. Osteoporosis is associated with an increased susceptibility to fragility fractures and can result in persistent pain and significant impairment in affected individuals. The primary method for diagnosing osteoporosis involves the assessment of bone mineral density (BMD) through the utilisation of dual energy x-ray absorptiometry (DEXA). The integration of a fracture risk assessment algorithm with bone mineral density (BMD) has led to significant progress in the diagnosis of osteoporosis. Given that osteoporosis is a chronic condition and multiple factors play an important role in maintaining bone mass, comprehending its underlying mechanism is crucial for developing more effective pharmaceutical interventions for the disease. The effective management of osteoporosis involves the utilisation of appropriate pharmacological agents in conjunction with suitable dietary interventions and lifestyle modifications. This review provides a comprehensive understanding of the types of osteoporosis and elucidates the currently available pharmacological treatment options and their related mechanism of action and usage.
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Affiliation(s)
- Rajeshwari Muniyasamy
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Inderchand Manjubala
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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21
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Hassan WNM, Al-Kaabi MM, Akram NN, Kassim MAK, Pantazi AC. Probiotics for Inflammatory Bowel Disease; A Deep Dive into their Impact on Disease Course and Associated Health Risks. Curr Med Chem 2024; 31:4807-4825. [PMID: 38693730 DOI: 10.2174/0109298673314861240429072352] [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: 03/06/2024] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 05/03/2024]
Abstract
To date, the underlying pathology of inflammatory bowel disease (IBD) is undetermined. Disturbance of intestinal gut microbiota was implicated in many health diseases, including IBD. Increasing evidence suggests that probiotics play a beneficial role in restoring the balance of the gut ecosystem. This review searched multiple databases for relevant works that examined probiotics' possible benefits in adults with IBD. Probiotic mode of action in ulcerative colitis patients and Crohn's disease were examined with respect to probiotic strain, their benefits, and their advantages in adult cases. Eligible studies for inclusion were assessed and analyzed. They were effective in reducing IBD disease course, inducing and maintaining remission, particularly for ulcerative colitis patients, with good efficacy and safety profile. However, the evidence for Crohn's disease was lacking. Probiotics positively affect IBD-related risks, reducing the risk of gastrointestinal malignancy and optimizing treating them. Additionally, they improved reduced fertility odds for both genders. The osteoporosis risk among IBD patients was also reduced, although the duration of use and dose were still not established. There was an encouraging role for them in reducing IBD -cardiovascular risks among cases with acute myocardial infarction and those with chronic heart failure. Finally, they had novel use in reducing IBD-related depression and improved overall mental health. In conclusion, we recommend probiotics as an adjuvant therapeutic option for IBD therapy for ulcerative colitis; however, their role in Crohn's disease needs further research.
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Carletti A, Gavaia PJ, Cancela ML, Laizé V. Metabolic bone disorders and the promise of marine osteoactive compounds. Cell Mol Life Sci 2023; 81:11. [PMID: 38117357 PMCID: PMC10733242 DOI: 10.1007/s00018-023-05033-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 10/12/2023] [Accepted: 11/05/2023] [Indexed: 12/21/2023]
Abstract
Metabolic bone disorders and associated fragility fractures are major causes of disability and mortality worldwide and place an important financial burden on the global health systems. These disorders result from an unbalance between bone anabolic and resorptive processes and are characterized by different pathophysiological mechanisms. Drugs are available to treat bone metabolic pathologies, but they are either poorly effective or associated with undesired side effects that limit their use. The molecular mechanism underlying the most common metabolic bone disorders, and the availability, efficacy, and limitations of therapeutic options currently available are discussed here. A source for the unmet need of novel drugs to treat metabolic bone disorders is marine organisms, which produce natural osteoactive compounds of high pharmaceutical potential. In this review, we have inventoried the marine osteoactive compounds (MOCs) currently identified and spotted the groups of marine organisms with potential for MOC production. Finally, we briefly examine the availability of in vivo screening and validation tools for the study of MOCs.
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Affiliation(s)
- Alessio Carletti
- Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Paulo Jorge Gavaia
- Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Associação Oceano Verde (GreenCoLab), Faro, Portugal
| | - Maria Leonor Cancela
- Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Faro, Portugal
| | - Vincent Laizé
- Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.
- Collaborative Laboratory for Sustainable and Smart Aquaculture (S2AQUAcoLAB), Olhão, Portugal.
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Martin TJ, Seeman E. Bone Remodeling and Modeling: Cellular Targets for Antiresorptive and Anabolic Treatments, Including Approaches Through the Parathyroid Hormone (PTH)/PTH-Related Protein Pathway. Neurospine 2023; 20:1097-1109. [PMID: 38171279 PMCID: PMC10762382 DOI: 10.14245/ns.2346966.483] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
Bone is continuously in a state of building and renewal, though the process of remodeling that takes place at many sites asynchronously throughout the skeleton, with bone formation and resorption equal at these sites (bone multicellular units). Remodeling takes place on bone surfaces, both on trabeculae and in the cortex, and serves the purposes of replacing old bone or that damaged by microfractures throughout the skeleton. The bone loss and consequent osteoporotic fractures that result from excess resorption over formation have mainly been prevented or treated by antiresorptive drugs that inhibit osteoclast formation and/or activity. Virtually all of the evidence leading to acceptance of antiresorptive drugs as treatment has depended upon their prevention of vertebral fractures. In recent decades, new prospects came of anabolic treatments that partly restore bone volume and microstructure restore bone that has been lost. The first of these was parathyroid hormone (PTH), shown by daily injection to increase markers of bone formation and prevent fractures. This field of interest enlarged with the discovery of PTH-related protein (PTHrP), so closely related in structure and action to PTH. The structural relationship between PTH and PTHrP is important in assessing their physiological and pharmacological roles, with the N-terminal domains of the 2 having virtually equal actions on target cells. Abaloparatide, a peptide analogue based on the structures of PTHrP and PTH, has been approved in some countries as a therapy for osteoporosis. Treatment through the PTH receptor activation pathway, and probably with any anabolic therapy, needs to be followed by antiresorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for antiresorptive drugs.
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Affiliation(s)
- Thomas John Martin
- Department of Medicine and St. Vincent’s Institute of Medical Research, University of Melbourne, Melbourne, Australia
| | - Ego Seeman
- Department of Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Australia
- Mary MacKillop Institute of Health Research, Australian Catholic University, Melbourne, Australia
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Ghanta P, Winschel T, Hessel E, Oyewumi O, Czech T, Oyewumi MO. Efficacy assessment of methylcellulose-based thermoresponsive hydrogels loaded with gallium acetylacetonate in osteoclastic bone resorption. Drug Deliv Transl Res 2023; 13:2533-2549. [PMID: 37014587 PMCID: PMC10469133 DOI: 10.1007/s13346-023-01336-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2023] [Indexed: 04/05/2023]
Abstract
Homeostatic imbalance involving progressive stimulation of osteoclast (OC) differentiation and function will lead to an increased risk of fragility fractures. In this regard, we investigated gallium acetylacetonate (GaAcAc) as a possible treatment for osteoclastic bone resorption. Further, the extent to which suitable delivery systems can enhance the therapeutic potential of GaAcAc was evaluated. GaAcAc solution (10-50 µg/mL) suppressed OC differentiation using murine monocytic RAW 264.7 or hematopoietic stem cells. Methylcellulose-based hydrogels were fabricated and characterized based on biocompatibility with bone cells, GaAcAc loading, and thermoresponsive behavior using storage (G') and loss (G″) moduli parameters. Compared to GaAcAc solution, hydrogels loaded with GaAcAc (GaMH) were more effective in suppressing OC differentiation and function. The number and extent of bone resorption pits from ex vivo studies were markedly reduced with GaMH treatment. Mechanistic assessment of GaMH efficacy showed superiority, compared to GaAcAc solution, in downregulating the expression of key markers involved in mediating OC differentiation (such as NFAT2, cFos, TRAF6, and TRAP) as well as in bone resorption by OCs (cathepsin K or CTSK). Additional studies (in vitro and in vivo) suggested that the performance of GaMH could be ascribed to controlled release of GaAcAc and the ability to achieve prolonged bio-retention after injection in BALB/c mice, which plausibly maximized the therapeutic impact of GaAcAc. Overall, the work demonstrated, for the first time, the therapeutic efficacy of GaAcAc and the therapeutic potential of GaMH delivery systems in osteoclastic bone resorption.
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Affiliation(s)
- Pratyusha Ghanta
- Advanced Drug Delivery Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA
- Department of Biomedical Sciences, Kent State University, Kent, OH, 44240, USA
| | - Timothy Winschel
- Advanced Drug Delivery Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA
| | - Evin Hessel
- Advanced Drug Delivery Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA
| | - Oluyinka Oyewumi
- Department of Geological Sciences, Central Connecticut State University, New Britain, CT, 06050, USA
| | - Tori Czech
- Advanced Drug Delivery Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA
| | - Moses O Oyewumi
- Advanced Drug Delivery Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
- Department of Biomedical Sciences, Kent State University, Kent, OH, 44240, USA.
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Wu Z, Zhu J, Wen Y, Lei P, Xie J, Shi H, Wu R, Lou X, Hu Y. Hmga1-overexpressing lentivirus protects against osteoporosis by activating the Wnt/β-catenin pathway in the osteogenic differentiation of BMSCs. FASEB J 2023; 37:e22987. [PMID: 37555233 DOI: 10.1096/fj.202300488r] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/26/2023] [Accepted: 05/09/2023] [Indexed: 08/10/2023]
Abstract
Postmenopausal osteoporosis is associated with bone formation inhibition mediated by the impaired osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs). However, identifying and confirming the essential genes in the osteogenic differentiation of BMSCs and osteoporosis remain challenging. The study aimed at revealing the key gene that regulated osteogenic differentiation of BMSCs and led to osteoporosis, thus exploring its therapeutic effect in osteoporosis. In the present study, six essential genes related to the osteogenic differentiation of BMSCs and osteoporosis were identified, namely, fibrillin 2 (Fbn2), leucine-rich repeat-containing 17 (Lrrc17), heat shock protein b7 (Hspb7), high mobility group AT-hook 1 (Hmga1), nexilin F-actin-binding protein (Nexn), and endothelial cell-specific molecule 1 (Esm1). Furthermore, the in vivo and in vitro experiments showed that Hmga1 expression was increased during the osteogenic differentiation of rat BMSCs, while Hmga1 expression was decreased in the bone tissue of ovariectomized (OVX) rats. Moreover, the expression of osteogenic differentiation-related genes, the activity of alkaline phosphatase (ALP), and the number of mineralized nodules were increased after Hmga1 overexpression, which was partially reversed by a Wnt signaling inhibitor (DKK1). In addition, after injecting Hmga1-overexpressing lentivirus into the bone marrow cavity of OVX rats, the bone loss, and osteogenic differentiation inhibition of BMSCs in OVX rats were partially reversed, while osteoclast differentiation promotion of BMSCs in OVX rats was unaffected. Taken together, the present study confirms that Hmga1 prevents OVX-induced bone loss by the Wnt signaling pathway and reveals that Hmga1 is a potential gene therapeutic target for postmenopausal osteoporosis.
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Affiliation(s)
- Zhixin Wu
- Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jiayong Zhu
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yinxian Wen
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Pengfei Lei
- Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Orthopedic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Xie
- Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Orthopedic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Haifei Shi
- Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ronghuan Wu
- Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xianfeng Lou
- Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yihe Hu
- Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Orthopedic Surgery, Xiangya Hospital, Central South University, Changsha, China
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Ahadzadeh Ardebili A, Fu T, Dunnewold N, Aghajafari F, Billington EO. Bisphosphonates Preserve Bone Mineral Density and Suppress Bone Turnover Markers in Early Menopausal Women: A Systematic Review and Meta-Analysis of Randomized Trials. JBMR Plus 2023; 7:e10748. [PMID: 37283657 PMCID: PMC10241086 DOI: 10.1002/jbm4.10748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/10/2023] [Accepted: 03/29/2023] [Indexed: 06/08/2023] Open
Abstract
Most women do not qualify for pharmacologic osteoporosis treatment until more than a decade after menopause, by which time they will have lost up to 30% of their bone mass and may have already sustained fractures. Short or intermittent courses of bisphosphonate therapy, initiated around the time of menopause, might prevent excessive bone loss and lower long-term fracture risk. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effects of nitrogen-containing bisphosphonates on fracture incidence, bone mineral density (BMD), and bone turnover markers in early menopausal women (ie, perimenopausal or <5 years postmenopausal) over ≥12 months. Medline, Embase, CENTRAL, and CINAHL were searched in July 2022. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Random effect meta-analysis was undertaken using RevMan v5.3. In total, 12 trials were included (n = 1722 women); five evaluated alendronate, three risedronate, three ibandronate, and one zoledronate. Four were at low risk of bias; eight raised some concerns. Fractures were infrequent in the three studies that reported them. Compared with placebo, bisphosphonates improved BMD over 12 months (mean percentage difference, 95% confidence interval [CI]) at the spine (4.32%, 95% CI, 3.10%-5.54%, p < 0.0001, n = 8 studies), the femoral neck (2.56%, 95% CI, 1.85%-3.27%, p = 0.001, n = 6 studies), and the total hip (1.22%, 95% CI 0.16%-2.28%, p = 0.002, n = 4 studies). Over treatment durations of 24 to 72 months, bisphosphonates improved BMD at the spine (5.81%, 95% CI 4.71%-6.91%, p < 0.0001, n = 8 studies), femoral neck (3.89%, 95% CI 2.73%-5.05%, p = 0.0001, n = 5 studies) and total hip (4.09%, 95% CI 2.81%-5.37%, p < 0.0001, n = 4 studies). Bisphosphonates reduced urinary N-telopeptide (-52.2%, 95% CI -60.3% to -44.2%, p < 0.00001, n = 3 studies) and bone-specific alkaline phosphatase (-34.2%, 95% CI -42.6% to -25.8%, p < 0.00001, n = 4 studies) more than placebo at 12 months. This systematic review and meta-analysis shows that bisphosphonates improve BMD and lower bone turnover markers in early menopause, warranting further investigation of these agents for osteoporosis prevention. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
| | - Timothy Fu
- Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Nicole Dunnewold
- Health Sciences LibraryUniversity of CalgaryCalgaryAlbertaCanada
| | | | - Emma O. Billington
- Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- McCaig Institute for Bone & Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
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27
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Walker MM, Oxenham MF, Vlok M, Matsumura H, Thi Mai Huong N, Trinh HH, Minh TT, Miszkiewicz JJ. Human femur morphology and histology variation with ancestry and behaviour in an ancient sample from Vietnam. Ann Anat 2023; 247:152054. [PMID: 36696927 DOI: 10.1016/j.aanat.2023.152054] [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: 09/12/2022] [Revised: 11/15/2022] [Accepted: 12/22/2022] [Indexed: 01/23/2023]
Abstract
BACKGROUND There is a genetic component to the minimum effective strain (MES)-a threshold which determines when bone will adapt to function-which suggests ancestry should play a role in bone (re)modelling. Further elucidating this is difficult in living human populations because of the high global genetic admixture. We examined femora from an anthropological skeletal assemblage (Mán Bạc, Vietnam) representing distinct ancestral groups. We tested whether femur morphological and histological markers of modelling and remodelling differed between ancestries despite their similar lifestyles. METHODS Static histomorphometry data collected from subperiosteal cortical bone of the femoral midshaft, and gross morphometric measures of femur robusticity, were studied in 17 individuals from the Mán Bạc collection dated to 1906-1523 cal. BC. This assemblage represents agricultural migrants with affinity to East Asian groups, who integrated with the local hunter-gatherers with affinity to Australo-Papuan groups during the mid-Holocene. Femur robusticity and histology data were compared between groups of 'Migrant' (n = 8), 'Admixed' (n = 4), and 'Local' (n = 5). RESULTS Local individuals had more robust femoral diaphyses with greater secondary osteon densities, and relatively large secondary osteon and Haversian canal parameters than the migrants. The Migrant group showed gracile femoral shafts with the least dense bone made up of small secondary osteons and Haversian canals. The Admixed individuals fell between the Migrant and Local categories in terms of their femoral data. However, we also found that measures of how densely bone is remodelled per unit area were in a tight range across all three ancestries. CONCLUSIONS Bone modelling and remodelling markers varied with ancestral histories in our sample. This suggests that there is an ancestry related predisposition to bone optimising its metabolic expenditure likely in relation to the MES. Our results stress the need to incorporate population genetic history into hierarchical bone analyses. Understanding ancestry effects on bone morphology has implications for interpreting biomechanical loading history in past and modern human populations.
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Affiliation(s)
- Meg M Walker
- School of Archaeology and Anthropology, Australian National University, 0200 Canberra, ACT, Australia.
| | - Marc F Oxenham
- School of Archaeology and Anthropology, Australian National University, 0200 Canberra, ACT, Australia; Department of Archaeology, University of Aberdeen, AB24 3FX Aberdeen, UK
| | - Melandri Vlok
- Sydney Southeast Asia Centre, The University of Sydney, Camperdown 2050, NSW, Australia
| | | | - Nguyen Thi Mai Huong
- Anthropological and Palaeoenvironmental Department, The Institute of Archaeology of Vietnam, Hanoi, Viet Nam
| | - Hoang Hiep Trinh
- Institute of Archaeology, Vietnam Academy of Social Science, 61 Phan Chu Trinh, Hanoi, Viet Nam
| | - Tran T Minh
- Anthropological and Palaeoenvironmental Department, The Institute of Archaeology of Vietnam, Hanoi, Viet Nam
| | - Justyna J Miszkiewicz
- School of Archaeology and Anthropology, Australian National University, 0200 Canberra, ACT, Australia; School of Social Science, University of Queensland, 4072 St Lucia, QLD, Australia.
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28
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The nanoformula of zoledronic acid and calcium carbonate targets osteoclasts and reverses osteoporosis. Biomaterials 2023; 296:122059. [PMID: 36848779 DOI: 10.1016/j.biomaterials.2023.122059] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023]
Abstract
Osteoporosis is known as an imbalance in bone catabolism and anabolism. Overactive bone resorption causes bone mass loss and increased incidence of fragility fractures. Antiresorptive drugs are widely used for osteoporosis treatment, and their inhibitory effects on osteoclasts (OCs) have been well established. However, due to the lack of selectivity, their off-target and side effects often bring suffering to patients. Herein, an OCs' microenvironment-responsive nanoplatform HA-MC/CaCO3/ZOL@PBAE-SA (HMCZP) is developed, consisting of succinic anhydride (SA)-modified poly(β-amino ester) (PBAE) micelle, calcium carbonate shell, minocycline-modified hyaluronic acid (HA-MC) and zoledronic acid (ZOL). Results indicate that HMCZP, as compared with the first-line therapy, could more effectively inhibit the activity of mature OCs and significantly reverse the systemic bone mass loss in ovariectomized mice. In addition, the OCs-targeted capacity of HMCZP makes it therapeutically efficient at sites of severe bone mass loss and allows it to reduce the adverse effects of ZOL, such as acute phase reaction. High-throughput RNA sequencing (RNA-seq) reveals that HMCZP could down-regulate a critical osteoporotic target, tartrate-resistant acid phosphatase (TRAP), as well as other potential therapeutical targets for osteoporosis. These results suggest that an intelligent nanoplatform targeting OCs is a promising strategy for osteoporosis therapy.
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Sun T, Yu X. FGF23 Actions in CKD-MBD and other Organs During CKD. Curr Med Chem 2023; 30:841-856. [PMID: 35761503 DOI: 10.2174/0929867329666220627122733] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/26/2022] [Accepted: 04/12/2022] [Indexed: 02/08/2023]
Abstract
Fibroblast growth factor 23 (FGF23) is a new endocrine product discovered in the past decade. In addition to being related to bone diseases, it has also been found to be related to kidney metabolism and parathyroid metabolism, especially as a biomarker and a key factor to be used in kidney diseases. FGF23 is upregulated as early as the second and third stages of chronic kidney disease (CKD) in response to relative phosphorus overload. The early rise of FGF23 has a protective effect on the body and is essential for maintaining phosphate balance. However, with the decline in renal function, eGFR (estimated glomerular filtration rate) declines, and the phosphorus excretion effect caused by FGF23 is weakened. It eventually leads to a variety of complications, such as bone disease (Chronic Kidney Disease-Mineral and Bone Metabolism Disorder), vascular calcification (VC), and more. Monoclonal antibodies against FGF23 are currently used to treat genetic diseases with increased FGF23. CKD is also a state of increased FGF23. This article reviews the current role of FGF23 in CKD and discusses the crosstalk between various organs under CKD conditions and FGF23. Studying the effect of hyperphosphatemia on different organs of CKD is important. The prospect of FGF23 for therapy is also discussed.
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Affiliation(s)
- Ting Sun
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, Rare Disease Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, Rare Disease Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
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Xu L, Hu YJ, Peng Y, Wang Z, Wang J, Lu WW, Tang B, Guo XE. Early zoledronate treatment inhibits subchondral bone microstructural changes in skeletally-mature, ACL-transected canine knees. Bone 2023; 167:116638. [PMID: 36464243 DOI: 10.1016/j.bone.2022.116638] [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: 09/04/2022] [Revised: 11/27/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022]
Abstract
Anterior cruciate ligament (ACL) tear leads to post-traumatic osteoarthritis (PTOA), a significant clinical burden worldwide that currently has no cure. Recent studies suggest a role of subchondral bone adaptations in the development of PTOA. Particularly, microstructural changes in the rod-and-plate microstructure of subchondral bone may precede and contribute to OA progression. In this study, we quantified microstructural changes in subchondral trabecular rods and plates after ACL-transection for the first time in the well-established preclinical canine model of PTOA and investigated the therapeutic potentials of a bisphosphonate (zoledronate) and NSAID treatment (meloxicam). Unilateral hindlimb ACL transection was performed on skeletally-mature (2-year-old, N = 20) and juvenile (10-month-old, N = 20) male beagles. Animals were assigned to 4 groups (N = 5): ACLT, un-operated control, ACLT with zoledronate, and ACLT with meloxicam treatment. Subchondral bone microstructure was evaluated by micro-computed tomography and cartilage integrity was evaluated histologically. We found that ACL-induced subchondral bone changes depended on skeletal maturity of animals. In mature animals, significant loss of trabecular plates that resulted in reduced PR ratio occurred at Month 1 and persisted until Month 8. Zoledronate treatment prevented trabecular plate loss while meloxicam treatment did not. Whether cartilage degeneration is also attenuated warrants further investigation. In juvenile animals that have not reached skeletal maturity, transient changes in trabecular plate and rod microstructure occurred at Month 3 but not Month 9. Neither zoledronate nor meloxicam treatment attenuated bone microstructural changes or cartilage damages. Findings from this study suggest that early inhibition of bone resorption by bisphosphonate after injury may be a promising therapeutic approach to prevent alterations in subchondral bone microstructure associated with PTOA. Our results further demonstrate that pathogenesis of PTOA may differ between adolescent and adult patients and therefore require distinct management strategies.
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Affiliation(s)
- Lei Xu
- Department of Biomedical Engineering, the Southern University of Science and Technology, Shenzhen, PR China; Department of Orthopeadics and Traumatology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong; Department of Orthopeadics and Traumatology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, PR China
| | - Yizhong Jenny Hu
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Ying Peng
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Zexi Wang
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Jingyi Wang
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - W William Lu
- Department of Orthopeadics and Traumatology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong
| | - Bin Tang
- Department of Biomedical Engineering, the Southern University of Science and Technology, Shenzhen, PR China
| | - X Edward Guo
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA.
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Fang Z, Cheng G, He M, Lin Y. CYP27A1 deficiency promoted osteoclast differentiation. PeerJ 2023; 11:e15041. [PMID: 36890868 PMCID: PMC9987298 DOI: 10.7717/peerj.15041] [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: 10/28/2022] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
Background The elevating osteoclast differentiation can lead to an imbalance in bone homeostasis, which was responsible for bone loss and bone diseases, such as osteoporosis. Multiple pathways and molecules have been involved in osteoclast formation, but the role of CYP27A1 in osteoclast differentiation has never been explored. Methods CYP27A1 deficient mice were constructed using CRISPR-Cas9 system. Osteoclast differentiation was detected by TRAP staining. Differentially expressed genes (DEGs) were identified using RNA-seq analysis and were confirmed by qRT-PCR and Western blot. Results The results showed that CYP27A1 knockout (KO) promoted osteoclast differentiation and bone loss. The transcriptomic analysis revealed that CYP27A1 KO led to differential expression of multiple genes, including ELANE, LY6C2, S100A9, GM20708, BGN, SPARC, and COL1A2, which were confirmed by qRT-PCR and Western blot. Enrichment analysis indicated that these differential genes were significantly associated with osteogenesis-related pathways, such as PPAR signaling, IL-17 signaling, and PI3K/AKT signaling, which were confirmed by qRT-PCR and Western blot. Conclusions These results suggested that CYP27A1 was involved in osteoclast differentiation, providing a novel therapeutic target for osteoclast-related diseases.
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Affiliation(s)
- Ziqi Fang
- Department of Clinical Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Guangdong Cheng
- Department of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Mengting He
- Department of Critical Care Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yanliang Lin
- Department of Clinical Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, China.,Department of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Engelmann J, Zarrer J, Gensch V, Riecken K, Berenbrok N, Luu TV, Beitzen-Heineke A, Vargas-Delgado ME, Pantel K, Bokemeyer C, Bhamidipati S, Darwish IS, Masuda E, Burstyn-Cohen T, Alberto EJ, Ghosh S, Rothlin C, Hesse E, Taipaleenmäki H, Ben-Batalla I, Loges S. Regulation of bone homeostasis by MERTK and TYRO3. Nat Commun 2022; 13:7689. [PMID: 36509738 PMCID: PMC9744875 DOI: 10.1038/s41467-022-33938-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 10/07/2022] [Indexed: 12/14/2022] Open
Abstract
The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.
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Affiliation(s)
- Janik Engelmann
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jennifer Zarrer
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Musculoskeletal Medicine, University Hospital, LMU Munich, Martinsried, Germany
- Musculoskeletal University Center Munich, University Hospital, LMU Munich, Martinsried, Germany
| | - Victoria Gensch
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Kristoffer Riecken
- Department of Stem Cell Transplantation, Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nikolaus Berenbrok
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - The Vinh Luu
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Antonia Beitzen-Heineke
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maria Elena Vargas-Delgado
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Klaus Pantel
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ihab S Darwish
- Rigel Pharmaceuticals, Inc., South San Francisco, CA, USA
| | - Esteban Masuda
- Rigel Pharmaceuticals, Inc., South San Francisco, CA, USA
| | - Tal Burstyn-Cohen
- Faculty of Dental Medicine, Institute for Dental Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Emily J Alberto
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Sourav Ghosh
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
- Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
| | - Carla Rothlin
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
| | - Eric Hesse
- Institute of Musculoskeletal Medicine, University Hospital, LMU Munich, Martinsried, Germany
- Musculoskeletal University Center Munich, University Hospital, LMU Munich, Martinsried, Germany
| | - Hanna Taipaleenmäki
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Musculoskeletal Medicine, University Hospital, LMU Munich, Martinsried, Germany
- Musculoskeletal University Center Munich, University Hospital, LMU Munich, Martinsried, Germany
| | - Isabel Ben-Batalla
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
- Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - Sonja Loges
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
- Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
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Yamashita Y, Hayashi M, Saito M, Nakashima T. Osteoblast Lineage Cell-derived Sema3A Regulates Bone Homeostasis Independently of Androgens. Endocrinology 2022; 163:6656579. [PMID: 35931046 DOI: 10.1210/endocr/bqac126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Indexed: 11/19/2022]
Abstract
Semaphorin 3A (Sema3A) coordinates bone resorption and formation under the control of estrogen signaling. However, the contribution of osteoblast lineage cell-derived Sema3A to vertebral homeostasis has remained unclear. Moreover, it is unknown whether androgen signaling is involved in Sema3A expression in osteoblast lineage cells. In this study, we show that osteoblast lineage cell-derived Sema3A plays a key role in bone homeostasis independent of androgen signaling. Sema3a deletion with Sp7-Cre did not alter the trabecular bone mass in lumbar vertebrae, along with there being no significant difference in Sema3a mRNA expression. In contrast, osteoblast lineage cell-specific deletion of Sema3A with BGLAP-Cre led to decreased bone volume in both long bones and lumbar vertebrae. In addition, osteoblast lineage cell-derived Sema3A was not involved in orchidectomy-induced bone loss because androgen deficiency did not affect Sema3A protein expression. Thus, these results indicate that Sema3A derived from osteoblast lineage cells acts as an osteoprotective factor, even in vertebrae, and its expression is controlled in an androgen-independent manner.
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Affiliation(s)
- Yu Yamashita
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Mikihito Hayashi
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Tomoki Nakashima
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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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: 8] [Impact Index Per Article: 2.7] [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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Tian S, Zou Y, Wang J, Li Y, An BZ, Liu YQ. Protective effect of Du-Zhong-Wan against osteoporotic fracture by targeting the osteoblastogenesis and angiogenesis couple factor SLIT3. JOURNAL OF ETHNOPHARMACOLOGY 2022; 295:115399. [PMID: 35649495 DOI: 10.1016/j.jep.2022.115399] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/12/2022] [Accepted: 05/19/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Du-Zhong-Wan (DZW) is a traditional Chinese medicine (TCM) composed of Eucommia ulmoides Oliv. and Dipsacus asper Wall. ex C.B. Clarke in the ratio 1:1. Based on the TCM theory, DZW nourishes the kidney to strengthen the bones. The literature research revealed that DZW possesses anti-fatigue, anti-depressant, and anti-osteoporotic properties. However, the action and mechanism of DZW on osteoporotic fracture remains slightly unclear. AIM OF THE STUDY To evaluate the pharmacological effect of DZW on ovariectomized mice with an open femoral fracture and reveal the underlying mechanism. MATERIALS AND METHODS We conducted ovariectomy for 5 weeks, followed by unilateral open transverse femoral fracture for another 3 weeks in C57BL/6 mice; during this process, DZW was administrated. The femur bone and vertebra tissues were collected and analyzed by micro-computed tomography, histomorphometry, mechanical strength testing, immunohistochemistry staining, and qRT-PCR analyses. In addition, alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were performed to determine the extent of osteoblastogenesis from bone marrow mesenchymal stem cells (BMSCs). Western blotting was performed to examine the protein expression. RESULTS DZW treatment significantly improved the bone histomorphometric parameters in mice undergoing ovariectomy when combined with the femoral fracture, including an increase in the bone volume, trabecular number, and bone formation rate and a decrease in the bone erosion area. Simultaneously, DZW treatment histologically promoted fractured callus formation. Mechanical strength testing revealed significantly higher stiffness and an ultimate load after treatment with DZW. The angiogenesis of H-type vessels was enhanced by DZW, as evidenced by increased levels of CD31 and endomucin (EMCN), the H-type vessel endothelium markers, at the fractured endosteum and metaphysis regions. Relative to the osteoporotic fracture mice, the DZW treatment group showed an increased proangiogenic factor SLIT3 level. The increased level of SLIT3 was also recorded during the process of DZW-stimulated osteoblastogenesis from BMSCs. CONCLUSIONS For the first time, we demonstrated that DZW promoted osteoporotic fracture healing by enhancing osteoblastogenesis and angiogenesis of the H-type vessels. This enhanced combination of osteoblastogenesis and angiogenesis was possibly related to the production of proangiogenic factor SLIT3 induced by DZW.
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Affiliation(s)
- Shuo Tian
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yixuan Zou
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Wang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yilin Li
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Bao-Zhen An
- The First Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Yan-Qiu Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China.
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36
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Jeong C, Ha J, Kim J, Lim Y, Kim MK, Kwon HS, Song KH, Kang MI, Baek KH. The efficacy of denosumab in Korean male patients with osteoporosis. Korean J Intern Med 2022; 37:1011-1020. [PMID: 36068717 PMCID: PMC9449194 DOI: 10.3904/kjim.2022.064] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/30/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS Despite the prominence of denosumab as the number one prescribed anti-osteoporosis drug in Korea, the effects of denosumab in male osteoporosis patients were not researched sufficiently. Moreover, concerns on rebound vertebral fractures associated with poor denosumab adherence exist. METHODS We retrospectively evaluated 147 Korean male osteoporosis patients treated with denosumab. After 12 months of treatment, 60 patients were lost during follow-up, and eight were excluded due to missing data. Out of the initial 147 patients, 79 were considered eligible for the analysis of the efficacy of denosumab. 54 patients were initially drug-naïve, and 25 had previously received bisphosphonate therapy. RESULTS In 54 drug-naïve patients, significant increases in bone mineral density (BMD) were observed in all measurement sites: 5.2% ± 3.7% in the lumbar spine, 2.3% ± 2.8% in the femoral neck, and 1.9% ± 2.8% in the total hip (p < 0.01, respectively). Trabecular bone score showed an increase of 0.5% ± 5.8% in drug-naïve patients. Likewise, in 25 patients with previous bisphosphonate treatment, increase in BMD were observed as well: 4.8% ± 3.5% in the lumbar spine, 1.4% ± 3.6% in the femoral neck, and 0.8% ± 2.1% in the total hip (p < 0.01, p = 0.06, p = 0.06, respectively). Significant declines of -55.1% ± 31.8% in C-terminal telopeptide of type 1 collagen (CTX), and -62.9% ± 21.3% in total procollagen 1 N-terminal propeptide (P1NP), in drug-naïve patients; and -37.7% ± 41.5%, in CTX and -55.4% ± 30.1%, in P1NP in patients with previous bisphosphonate treatment were exhibited after 12 months of treatment. The adherence rates of the second and third dosing schedules were 79.9% and 56.8%, respectively. CONCLUSION Our study indicates that denosumab is effective in increasing BMD in Korean osteoporosis males regardless of prior bisphosphonate treatment.
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Affiliation(s)
- Chaiho Jeong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu,
Korea
| | - Jeonghoon Ha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Jinyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Yejee Lim
- Division of General Internal Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam,
Korea
| | - Mee Kyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Hyuk-Sang Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Ki-Ho Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Moo Il Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Ki-Hyun Baek
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
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Sharma K, Awasthi P, Prakash R, Khanka S, Bajpai R, Sahasrabuddhe AA, Goel A, Singh D. Maintenance of increased bone mass after PTH withdrawal by sequential medicarpin treatment via augmentation of cAMP-PKA pathway. J Cell Biochem 2022; 123:1762-1779. [PMID: 35959633 DOI: 10.1002/jcb.30313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 11/09/2022]
Abstract
Osteoporosis is a metabolic bone disorder associated with impaired bone microarchitecture leading to fragility fractures. Long-term usage of parathyroid hormone (PTH) enhances bone resorption and leads to osteosarcoma in rats which limits its exposure to maximum 2 years in human. Notably, the anabolic effects of PTH do not endure in the absence of sustained administration. Studies in our lab identified osteogenic and antiresorptive activity in medicarpin, a phytoestrogen belonging to the pterocarpan class. Considering dual-acting property of medicarpin and limitations of PTH therapy, we envisaged that medicarpin sequential treatment after PTH withdrawal could serve as promising therapeutic approach for osteoporosis treatment. As PTH exerts its bone anabolic effect by increasing osteoblast survival, our study aims to determine whether medicarpin amplifies this effect of PTH. Our results show that PTH withdrawal led to reduced bone mineral density and bone parameters, while sequential treatment of medicarpin after PTH withdrawal significantly enhanced these parameters. Remarkably, these effects were more pronounced than 8-week PTH treatment. Sequential therapy also significantly increased P1NP levels and decreased CTX levels and TRAP positive cells compared to PTH 8W group where CTX levels were quite high due to bone resorptive action of PTH. Protein expression studies revealed that medicarpin along with PTH betters the antiapoptotic potential compared to PTH alone, through augmentation of cyclic adenosine monophosphate-PKA-CREB pathway. These results proclaim that medicarpin sequential treatment prevented the reduction in bone accrual and strength accompanying PTH withdrawal and also aided in antiapoptotic role of PTH. The study points toward the potential use of medicarpin as a replacement therapeutic option postdiscontinuation of PTH.
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Affiliation(s)
- Kriti Sharma
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Pallavi Awasthi
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India.,Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Ravi Prakash
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Sonu Khanka
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Ranju Bajpai
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Amogh A Sahasrabuddhe
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India.,Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Atul Goel
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India.,Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Divya Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
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Estrogen Receptor 1 (ESR1) and the Wnt/β-Catenin Pathway Mediate the Effect of the Coumarin Derivative Umbelliferon on Bone Mineralization. Nutrients 2022; 14:nu14153209. [PMID: 35956385 PMCID: PMC9370350 DOI: 10.3390/nu14153209] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Bone physiology is regulated by osteoblast and osteoclast activities, both involved in the bone remodeling process, through deposition and resorption mechanisms, respectively. The imbalance between these two phenomena contributes to the onset of bone diseases. Among these, osteoporosis is the most common metabolic bone disorder. The therapies currently used for its treatment include antiresorptive and anabolic agents associated with side effects. Therefore, alternative therapeutic approaches, including natural molecules such as coumarin and their derivatives, have recently shown positive results. Thus, our proposal was to investigate the effect of the coumarin derivative umbelliferon (UF) using an interesting model of human osteoblasts (hOBs) isolated from osteoporotic patients. UF significantly improved the activity of osteoporotic-patient-derived hOBs via estrogen receptor 1 (ESR1) and the downstream activation of β-catenin pathway. Additionally, hOBs were co-cultured in microgravity with human osteoclasts (hOCs) using a 3D system bioreactor, able to reproduce the bone remodeling unit in bone loss conditions in vitro. Notably, UF exerted its anabolic role by reducing the multinucleated cells. Overall, our study confirms the potential efficacy of UF in bone health, and identified, for the first time, a prospective alternative natural compound useful to prevent/treat bone loss diseases such as osteoporosis.
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Jin F, Zhu Y, Liu M, Wang R, Cui Y, Wu Y, Liu G, Wang Y, Wang X, Ren Z. Babam2 negatively regulates osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription. Int J Biol Sci 2022; 18:4482-4496. [PMID: 35864959 PMCID: PMC9295054 DOI: 10.7150/ijbs.72487] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/26/2022] [Indexed: 11/21/2022] Open
Abstract
Osteoclast-mediated excessive bone resorption was highly related to diverse bone diseases including osteoporosis. BRISC and BRCA1-A complex member 2 (Babam2) was an evolutionarily conserved protein that is highly expressed in bone tissues. However, whether Babam2 is involved in osteoclast formation is still unclear. In this study, we identify Babam2 as an essential negative regulator of osteoclast formation. We demonstrate that Babam2 knockdown significantly accelerated osteoclast formation and activity, while Babam2 overexpression blocked osteoclast formation and activity. Moreover, we demonstrate that the bone resorption activity was significantly downregulated in Babam2-transgenic mice as compared with wild-type littermates. Consistently, the bone mass of the Babam2-transgenic mice was increased. Furthermore, we found that Babam2-transgenic mice were protected from LPS-induced bone resorption activation and thus reduced the calvarial bone lesions. Mechanistically, we demonstrate that the inhibitory effects of Babam2 on osteoclast differentiation were dependent on Hey1. As silencing Hey1 largely diminished the effects of Babam2 on osteoclastogenesis. Finally, we show that Babam2 interacts with Hey1 to inhibit Nfatc1 transcription. In sum, our results suggested that Babam2 negatively regulates osteoclastogenesis and bone resorption by interacting with Hey1 to inhibit Nfatc1 transcription. Therefore, targeting Babam2 may be a novel therapeutic approach for osteoclast-related bone diseases.
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Affiliation(s)
- Fujun Jin
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing 100191, China.,Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yexuan Zhu
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Meijing Liu
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing 100191, China
| | - Rongze Wang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yi Cui
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing 100191, China
| | - Yanting Wu
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Gang Liu
- Department of Rehabilitation Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yifei Wang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Xiaogang Wang
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing 100191, China
| | - Zhe Ren
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
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A 5-year retrospective cohort study of denosumab induced medication related osteonecrosis of the jaw in osteoporosis patients. Sci Rep 2022; 12:8641. [PMID: 35606457 PMCID: PMC9126865 DOI: 10.1038/s41598-022-11615-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/20/2022] [Indexed: 11/08/2022] Open
Abstract
AbstractDenosumab has been suggested as a first-line therapy for osteoporotic patients. However, a standardized protocol for the prevention of denosumab induced medication-related osteonecrosis of the jaw (MRONJ) has not yet been established. The purpose of this study was to report denosumab induced MRONJ cases, and investigate the factors affecting the occurrence of MRONJ in patients who underwent denosumab and invasive dental treatment (especially tooth extraction) between October 2016 and March 2020. Four of the 98 patients developed MRONJ before and after tooth extraction. The participants were divided into two groups: receiving only denosumab (n = 51) and receiving bisphosphonate as first treatment and denosumab as second treatment (n = 47). There was no significant difference between groups in the occurrence of MRONJ and factors affecting MRONJ. Two out of 4 patients developed MRONJ regardless of invasive treatment after denosumab administration and proceeded with extraction; one patient developed MRONJ after denosumab administration and extraction. The other patient underwent a tooth extraction without osteoporosis treatment, and non-identified MRONJ developed after denosumab administration. MRONJ cases reported in this study show that MRONJ can develop as chronic inflammation without invasive dental treatment; therefore, implementing preventive dental treatment before initiating denosumab treatment is necessary to reduce the occurrence of MRONJ.
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Hoenig T, Ackerman KE, Beck BR, Bouxsein ML, Burr DB, Hollander K, Popp KL, Rolvien T, Tenforde AS, Warden SJ. Bone stress injuries. Nat Rev Dis Primers 2022; 8:26. [PMID: 35484131 DOI: 10.1038/s41572-022-00352-y] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/11/2022] [Indexed: 01/11/2023]
Abstract
Bone stress injuries, including stress fractures, are overuse injuries that lead to substantial morbidity in active individuals. These injuries occur when excessive repetitive loads are introduced to a generally normal skeleton. Although the precise mechanisms for bone stress injuries are not completely understood, the prevailing theory is that an imbalance in bone metabolism favours microdamage accumulation over its removal and replacement with new bone via targeted remodelling. Diagnosis is achieved by a combination of patient history and physical examination, with imaging used for confirmation. Management of bone stress injuries is guided by their location and consequent risk of healing complications. Bone stress injuries at low-risk sites typically heal with activity modification followed by progressive loading and return to activity. Additional treatment approaches include non-weight-bearing immobilization, medications or surgery, but these approaches are usually limited to managing bone stress injuries that occur at high-risk sites. A comprehensive strategy that integrates anatomical, biomechanical and biological risk factors has the potential to improve the understanding of these injuries and aid in their prevention and management.
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Affiliation(s)
- Tim Hoenig
- Department of Trauma and Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Kathryn E Ackerman
- Wu Tsai Female Athlete Program, Boston Children's Hospital, Boston, MA, USA.,Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Belinda R Beck
- School of Health Sciences & Social Work, Griffith University, Gold Coast, Queensland, Australia.,Menzies Health Institute Queensland, Gold Coast, Queensland, Australia.,The Bone Clinic, Brisbane, Queensland, Australia
| | - Mary L Bouxsein
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Orthopedic Surgery, Harvard Medical School and Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - David B Burr
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Karsten Hollander
- Institute of Interdisciplinary Exercise Science and Sports Medicine, MSH Medical School Hamburg, Hamburg, Germany
| | - Kristin L Popp
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Tim Rolvien
- Department of Trauma and Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Adam S Tenforde
- Spaulding Rehabilitation Hospital, Department of Physical Medicine and Rehabilitation, Harvard Medical School, Charlestown, MA, USA.
| | - Stuart J Warden
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA. .,Department of Physical Therapy, School of Health & Human Sciences, Indiana University, Indianapolis, IN, USA. .,La Trobe Sport and Exercise Medicine Research Centre, La Trobe University, Bundoora, Victoria, Australia.
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Ebeling PR, Nguyen HH, Aleksova J, Vincent AJ, Wong P, Milat F. Secondary Osteoporosis. Endocr Rev 2022; 43:240-313. [PMID: 34476488 DOI: 10.1210/endrev/bnab028] [Citation(s) in RCA: 150] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Indexed: 02/07/2023]
Abstract
Osteoporosis is a global public health problem, with fractures contributing to significant morbidity and mortality. Although postmenopausal osteoporosis is most common, up to 30% of postmenopausal women, > 50% of premenopausal women, and between 50% and 80% of men have secondary osteoporosis. Exclusion of secondary causes is important, as treatment of such patients often commences by treating the underlying condition. These are varied but often neglected, ranging from endocrine to chronic inflammatory and genetic conditions. General screening is recommended for all patients with osteoporosis, with advanced investigations reserved for premenopausal women and men aged < 50 years, for older patients in whom classical risk factors for osteoporosis are absent, and for all patients with the lowest bone mass (Z-score ≤ -2). The response of secondary osteoporosis to conventional anti-osteoporosis therapy may be inadequate if the underlying condition is unrecognized and untreated. Bone densitometry, using dual-energy x-ray absorptiometry, may underestimate fracture risk in some chronic diseases, including glucocorticoid-induced osteoporosis, type 2 diabetes, and obesity, and may overestimate fracture risk in others (eg, Turner syndrome). FRAX and trabecular bone score may provide additional information regarding fracture risk in secondary osteoporosis, but their use is limited to adults aged ≥ 40 years and ≥ 50 years, respectively. In addition, FRAX requires adjustment in some chronic conditions, such as glucocorticoid use, type 2 diabetes, and HIV. In most conditions, evidence for antiresorptive or anabolic therapy is limited to increases in bone mass. Current osteoporosis management guidelines also neglect secondary osteoporosis and these existing evidence gaps are discussed.
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Affiliation(s)
- Peter R Ebeling
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia
| | - Hanh H Nguyen
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Department of Endocrinology and Diabetes, Western Health, Victoria 3011, Australia
| | - Jasna Aleksova
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Amanda J Vincent
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria 3168, Australia
| | - Phillip Wong
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Frances Milat
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
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Choe HJ, Koo BK, Yi KH, Kong SH, Kim JH, Shin CS, Chai JW, Kim SW. Skeletal effects of combined bisphosphonates treatment and parathyroidectomy in osteoporotic patients with primary hyperparathyroidism. J Bone Miner Metab 2022; 40:292-300. [PMID: 34761302 DOI: 10.1007/s00774-021-01279-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 10/11/2021] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Bone loss caused by primary hyperparathyroidism (PHPT) is an indication for parathyroidectomy (PTX). However, whether adding bisphosphonates would be superior to PTX alone to increase bone mass remains unclear. We thus aimed to compare the skeletal effects of the combination treatment of bisphosphonates and PTX with PTX alone. MATERIALS AND METHODS In this retrospective analysis, bone mineral density (BMD) changes after 1 year of combination treatment and PTX alone were compared. We also analyzed the correlation between changes in serum biochemical parameters and BMD after 1 year of treatment in both groups. RESULTS The baseline characteristics of patients treated with PTX alone (n = 24) and combination treatment (n = 26) were comparable. BMD significantly increased after 1 year of treatment in both groups (all p < 0.001), and the increase in BMD at the femur neck was higher in the PTX alone group than in the combination group (p = 0.011). There was a decreasing trend in serum alkaline phosphatase (ALP) levels in PTX alone compared to the combination treatment group (p = 0.053). In the study cohort, lower BMD and higher ALP levels at baseline were associated with higher 1-year BMD changes at all sites. Interestingly, a significant association was found between changes in ALP and BMD at the femur neck in the PTX alone group (p = 0.003), but abolished in the combination group (p = 0.946). CONCLUSIONS There is no additional benefit of BMD in combination treatment with bisphosphonates and PTX over PTX alone in osteoporotic patients with PHPT. Combined bisphosphonate treatment might interfere with the increase in bone mass caused by PTX.
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Affiliation(s)
- Hun Jee Choe
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea
- Division of Endocrinology and Metabolism, Seoul National University Hospital, Seoul, 03080, Korea
| | - Bo Kyung Koo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea
- Division of Endocrinology and Metabolism, Seoul Metropolitan Government Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Republic of Korea
| | - Ka Hee Yi
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea
- Division of Endocrinology and Metabolism, Seoul Metropolitan Government Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Republic of Korea
| | - Sung Hye Kong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea
- Division of Endocrinology and Metabolism, Seoul National University Hospital, Seoul, 03080, Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea
- Division of Endocrinology and Metabolism, Seoul National University Hospital, Seoul, 03080, Korea
| | - Chan Soo Shin
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea
- Division of Endocrinology and Metabolism, Seoul National University Hospital, Seoul, 03080, Korea
| | - Jee Won Chai
- Department of Radiology, Seoul National University College of Medicine, Seoul, 03080, Korea
- Department of Radiology, Seoul Metropolitan Government Boramae Medical Center, Seoul, 07061, Korea
| | - Sang Wan Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
- Division of Endocrinology and Metabolism, Seoul Metropolitan Government Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Republic of Korea.
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Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo. Nat Commun 2022; 13:1066. [PMID: 35210428 PMCID: PMC8873258 DOI: 10.1038/s41467-022-28673-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 02/07/2022] [Indexed: 12/18/2022] Open
Abstract
Bone metabolism is regulated by the cooperative activity between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the mechanisms mediating the switch between the osteoblastic and osteoclastic phases have not been fully elucidated. Here, we identify a specific subset of mature osteoblast-derived extracellular vesicles that inhibit bone formation and enhance osteoclastogenesis. Intravital imaging reveals that mature osteoblasts secrete and capture extracellular vesicles, referred to as small osteoblast vesicles (SOVs). Co-culture experiments demonstrate that SOVs suppress osteoblast differentiation and enhance the expression of receptor activator of NF-κB ligand, thereby inducing osteoclast differentiation. We also elucidate that the SOV-enriched microRNA miR-143 inhibits Runt-related transcription factor 2, a master regulator of osteoblastogenesis, by targeting the mRNA expression of its dimerization partner, core-binding factor β. In summary, we identify SOVs as a mode of cell-to-cell communication, controlling the dynamic transition from bone-forming to bone-resorbing phases in vivo.
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45
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Hu YJ, Chines A, Shi Y, Seeman E, Guo XE. The effect of denosumab and alendronate on trabecular plate and rod microstructure at the distal tibia and radius: A post-hoc HR-pQCT study. Bone 2022; 154:116187. [PMID: 34530172 DOI: 10.1016/j.bone.2021.116187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 09/02/2021] [Accepted: 09/09/2021] [Indexed: 01/23/2023]
Abstract
BACKGROUND Age-related trabecular microstructural deterioration and conversion from plate-like trabeculae to rod-like trabeculae occur because of unbalanced rapid remodeling. As denosumab achieves greater remodeling suppression and lower cortical porosity than alendronate, we hypothesized that denosumab might also preserve trabecular plate microstructure, bone stiffness and strength more effectively than alendronate. METHODS In this post hoc analysis of a phase 2 study, postmenopausal women randomized to placebo (P, n = 74), denosumab (D, n = 72), or alendronate (A, n = 68). HR-pQCT scans of the distal radius and tibia were performed at baseline and Month-12 (M12). Trabecular compartment was subjected to Individual Trabecula Segmentation while finite element analysis was performed to estimate stiffness and strength. Percent change from baseline at M12 of each parameter was compared between patient groups. RESULTS At the distal tibia, in the placebo group, plate surface area (pTb.S, -1.3%) decreased while rod bone volume fraction (rBV/TV, +4.5%) and number (rTb.N, +2.1%) increased. These changes were prevented by denosumab but persisted despite alendronate therapy (pTb.S: -1.7%; rBV/TV: +6.9%; rTb.N: +3.0%). Both treatments improved whole bone stiffness (D: +3.1%; A: +1.8%) and failure load (D: +3.0%; A: +2.2%); improvements using denosumab was significant compared to placebo (stiffness: p = 0.004; failure load: p = 0.003). At the distal radius, denosumab increased total trabecular bone volume fraction (BV/TV, +3.4%) and whole bone failure load (+4.0%), significantly different from placebo (BV/TV: p = 0.044; failure load: p = 0.046). Significantly different effects of either drug on plate and rod microstructure were not detected. CONCLUSIONS Denosumab preserved trabecular plate microstructure. Alendronate did not. However, estimated strength did not differ between denosumab and alendronate treated groups.
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Affiliation(s)
- Yizhong Jenny Hu
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | | | | | - Ego Seeman
- Departments of Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Australia; Mary MacKillop Institute of Healthy Aging, Australian Catholic University, Melbourne, Australia
| | - X Edward Guo
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA.
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46
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Lee A, Yang H, Kim T, Ha H, Hwang YH. Identification and pharmacokinetics of bioavailable anti-resorptive phytochemicals after oral administration of Psoralea corylifolia L. Biomed Pharmacother 2021; 144:112300. [PMID: 34653758 DOI: 10.1016/j.biopha.2021.112300] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/27/2021] [Accepted: 10/05/2021] [Indexed: 01/16/2023] Open
Abstract
Osteoporosis and resulting bone fractures are the major health issues associated with morbidity in the aging population; however, there is no effective treatment that does not cause severe side effects. In East Asia, dried seeds of Psoralea corylifolia L. (PC) have traditionally been used as an herbal medicine to manage urinary tract, cutaneous, and gastrointestinal disorders, as well as bone health. However, the mechanism of action and active biocomponents of PC are unclear. Here, we adopted a pharmacokinetic (PK) study aiming to identify the bioavailable phytochemicals in aqueous and ethanolic extracts of PC (APC) and (EPC), respectively. In addition, we aimed to determine anti-resorptive constituents of PC, which accounted for its beneficial effects on bone health. To this end, we used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A rapid, sensitive, and reliable UPLC-MS/MS method was developed and determined the 17 PC ingredients. In the PK study, nine components (two chalcones, two coumarins, one coumestan, two flavonoids, and two isoflavonoids) were observed between 36 and 48 h after oral administration of APC or EPC. Among the bioavailable ingredients, four PC constituents (psoralidin, isobavachin, corylifol A, and neobavaisoflavone) inhibited M-CSF-and RANKL-induced osteoclast differentiation in bone marrow-derived macrophages. In addition, two chalcones and two isoflavonoids markedly inhibited cathepsin K activity, and their binding modes to cathepsin K were determined by molecular docking. In summary, our data suggest that bioavailable multicomponents of PC could contribute to the management of bone health.
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Affiliation(s)
- Ami Lee
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; University of Science & Technology (UST), Korean Convergence Medicine Major KIOM, Daejeon 34054, Republic of Korea
| | - Hyun Yang
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
| | - Taesoo Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
| | - Hyunil Ha
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea.
| | - Youn-Hwan Hwang
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; University of Science & Technology (UST), Korean Convergence Medicine Major KIOM, Daejeon 34054, Republic of Korea.
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ULK1 Suppresses Osteoclast Differentiation and Bone Resorption via Inhibiting Syk-JNK through DOK3. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2896674. [PMID: 34820053 PMCID: PMC8608530 DOI: 10.1155/2021/2896674] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/17/2021] [Accepted: 10/29/2021] [Indexed: 12/30/2022]
Abstract
Bone resorption diseases, including osteoporosis, are usually caused by excessive osteoclastogenesis. Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian serine/threonine kinase, may participate in the regulation of bone homeostasis and osteolytic metastasis. In this study, ULK1 expression during osteoclastogenesis was detected with RT-PCR. We knocked down or overexpressed ULK1 through siRNA or lentiviral transduction in bone marrow macrophage (BMM). TRAP and phalloidin staining were performed to detect the osteoclastogenesis activity. Ovariectomized (OVX) mouse model of osteoporosis and a mouse of model osteoclast-induced bone resorption were applied to explore the role of ULK1 in bone resorption in vivo. The results showed that ULK1 expression was downregulated during osteoclast differentiation and was clinically associated with osteoporosis. ULK1 inhibited osteoclast differentiation in vitro. Knockdown of ULK1 expression activated phosphorylation of c-Jun N-terminal kinase (JNK) and spleen tyrosine kinase (Syk). Docking protein 3 (DOK3) was coexpressed with ULK1 during osteoclastogenesis. Downregulation of DOK3 offsets the effect of ULK1 on osteoclastogenesis and induced phosphorylation of JNK and Syk. Activation of ULK1 impeded bone loss in OVX mice with osteoporosis. Additionally, upregulation of ULK1 inhibited osteoclast-induced bone resorption in vivo. Therefore, our study reveals a novel ULK1/DOK3/Syk axis that regulates osteoclast differentiation and bone resorption, and targeting ULK1 is a potential therapeutic strategy for osteoporosis.
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Chen X, Zhu W, Xu R, Shen X, Fu Y, Cheng J, Liu L, Jiang H. Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw. Front Cell Dev Biol 2021; 9:770899. [PMID: 34805177 PMCID: PMC8595285 DOI: 10.3389/fcell.2021.770899] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/06/2021] [Indexed: 11/19/2022] Open
Abstract
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe side effect of long-term administration of bisphosphonates such as zoledronic acid (ZA), but its pathogenesis remains unclear. Impairment of the clearance of apoptotic cells (termed “efferocytosis”) by ZA may be associated with the pathogenesis of BRONJ. The aim of this study was to investigate whether ZA might inhibit macrophage efferocytosis and promote osteocytic apoptosis, and the underlying mechanisms responsible for the disturbing balance between clean and generation of osteocytic apoptosis. We found that ZA significantly promoted the apoptosis of osteocyte and pre-osteoblast via BRONJ mouse models and in vitro MC3T3-E1 but also inhibited the efferocytosis of macrophage on apoptotic cells. Moreover, supplement with geranylgeraniol (GGOH), a substrate analog for geranylgeranylation of Rac1, could restore Rac1 homeostasis and rescue macrophage efferocytosis. GGOH partially inhibits MC3T3-E1 apoptosis induced by ZA via downregulation of Rac1/JNK pathway. We also examined the Rac1 distribution and activation conditions in bone marrow-derived macrophages (BMDMs) and MC3T3-E1 under ZA treatment, and we found that ZA impaired Rac1 migration to BMDM membrane, leading to round appearance with less pseudopodia and efferocytosis inhibition. Moreover, ZA simultaneously activated Rac1, causing overexpression of P-JNK and cleaved caspase 3 in MC3T3-E1. Finally, the systemic administration of GGOH decreased the osteocytic apoptosis and improved the bone healing of the extraction sockets in BRONJ mouse models. Taken together, our findings provided a new insight and experimental basis for the application of GGOH in the treatment of BRONJ.
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Affiliation(s)
- Xin Chen
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.,Department of Stomatology, Jiangyin People's Hospital, Wuxi, China
| | - Weiwen Zhu
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.,Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Rongyao Xu
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Xin Shen
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Yu Fu
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Jie Cheng
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Laikui Liu
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.,Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Hongbing Jiang
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
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Yang C, Yang P, Liu P, Wang H, Ke E, Li K, Yan H. Targeting Filamin A alleviates ovariectomy-induced bone loss in mice via the WNT/β-catenin signaling pathway. Cell Signal 2021; 90:110191. [PMID: 34774991 DOI: 10.1016/j.cellsig.2021.110191] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/22/2021] [Accepted: 11/08/2021] [Indexed: 11/03/2022]
Abstract
Osteoporosis (OP) is a worldwide prevalent chronic metabolic bone disease, causing by a disruption of the balance between bone resorption and formation. Estrogen deficiency and aging are the main causes for disturbances in bone remodeling activity and bone loss, however, the mechanisms underlying bone remodeling regulation require clarification if novel targets for OP treatment are to be identified. In this investigation, we showed that filamin A (FLNA) accumulated in osteoblasts (OBs) and osteoclasts (OC) in bone from human OP samples, and mice with age-related and postmenopausal OP. FLNA negatively modulated in vitro osteogenic differentiation and positively promoted RANKL-induced osteoclastic differentiation. Mechanistically, FLNA interacted with low-density lipoprotein receptor-related proteins 6 (LRP6) to inhibit β-catenin expression, and enhanced nuclear factor of activated T cell c1 (NFATc1)-dependent osteoclastogenic gene expression to inhibit osteogenesis, and promote osteoclastogenesis. Inhibiting FLNA with calpeptin activated WNT/β-catenin signaling, resulting in prominent protective effects of bone loss in ovariectomy (OVX)-induced postmenopausal OP mice. Our findings revealed that FLNA not only participated in OP pathogenesis, but could be a new target to stimulate bone formation and inhibit bone resorption. Targeting FLNA with calpeptin may be a promising therapeutic approach for postmenopausal OP in the future.
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Affiliation(s)
- Changsheng Yang
- Department of Spine Surgery, The Third Affiliated Hospital of Southern Medical University, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, Guangdong Province 510000, China
| | - Panpan Yang
- Academy of Orthopedics Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province 510000, China
| | - Peilin Liu
- Academy of Orthopedics Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province 510000, China
| | - Hong Wang
- Academy of Orthopedics Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province 510000, China
| | - Ee Ke
- Guangdong Provincial People's Hospital, Guangdong, Academy of Medical Sciences, Guangzhou 510080, China.
| | - Kai Li
- Academy of Orthopedics Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province 510000, China.
| | - Huibo Yan
- Department of Spine Surgery, The Third Affiliated Hospital of Southern Medical University, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, Guangdong Province 510000, China.
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Yu P, Liu Y, Xie J, Li J. Spatiotemporally controlled calcitonin delivery: Long-term and targeted therapy of skeletal diseases. J Control Release 2021; 338:486-504. [PMID: 34481022 DOI: 10.1016/j.jconrel.2021.08.056] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 02/05/2023]
Abstract
Bone is a connective tissue that support the entire body and protect the internal organs. However, there are great challenges on curing intractable skeletal diseases such as hypercalcemia, osteoporosis and osteoarthritis. To address these issues, calcitonin (CT) therapy is an effective treatment alternative to regulate calcium metabolism and suppress inflammation response, which are closely related to skeletal diseases. Traditional calcitonin formulation requires frequent administration due to the low bioavailability resulting from the short half-life and abundant calcitonin receptors distributed through the whole body. Therefore, long-term and targeted calcitonin delivery systems (LCDS and TCDS) have been widely explored as the popular strategies to overcome the intrinsic limitations of calcitonin and improve the functions of calcium management and inflammation inhibition in recent years. In this review, we first explain the physiological effects of calcitonin on bone remodeling: (i) inhibitory effects on osteoclasts and (ii) facilitated effects on osteoblasts. Then we summarized four strategies for spatiotemporally controlled delivery of calcitonin: micro-/nanomedicine (e.g. inorganic micro-/nanomedicine, polymeric micro-/nanomedicine and supramolecular assemblies), hydrogels (especially thermosensitive hydrogels), prodrug (PEGylation and targeting design) and hybrid biomaterials. Subsequently, we discussed the application of LCDS and TCDS in treating hypercalcemia, osteoporosis, and arthritis. Understanding and analyzing these advanced calcitonin delivery applications are essential for future development of calcitonin therapies toward skeletal diseases with superior efficacy in clinic.
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Affiliation(s)
- Peng Yu
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, PR China
| | - Yanpeng Liu
- Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, PR China
| | - Jing Xie
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, PR China.
| | - Jianshu Li
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, PR China; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Med-X Center for Materials, Sichuan University, Chengdu 610041, PR China.
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