Osteoporotic fracture: ‘Three-in-one’ bone-repair strategy

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Osteoporosis, prevalent in the elderly, is associated with an increased risk of osteoporotic fracture. Such fractures can have severe consequences for patients – even death. Based on their extensive knowledge and clinical experience, Professor Jiacan Su and colleagues at the Shanghai University Institute of Translational Medicine, China, propose a ‘three-in-one’ bone-repair strategy. There are three cores to their approach, which are to treat osteoporosis, emphasise bone grafting, and accelerate fracture healing. They have one goal for all osteoporotic patients: ‘better bone healing, better life’.
Our bones, the vital supporting infrastructure of our body, are continuously remodelling through two balancing processes: bone formation and resorption. Bone formation is driven by osteoblasts and bone resorption by osteoclasts. An imbalance in these processes can lead to bone disorders. Diseases such as osteoporosis, rheumatoid arthritis, and osteopetrosis are bone resorption disorders. Worldwide, 200 million people have osteoporosis, a condition characterised by sustained bone loss that causes weak and brittle bones. One approach for targeting bone resorption disorders is to inhibit the activation of osteoclasts, which are overactive in these diseases. Drugs targeting this mechanism are in use but have side effects and low specificity for bone, leading to concomitant effects on other organs. Such drugs may inhibit bone resorption, but also have detrimental effects on bone remodelling and bone formation. Researchers are therefore searching for new treatments with higher specificity for bone and without negative side effects.

Professor Jiacan Su proposes a ‘three-in-one’ bone-repair strategy.

Due to diminished bone strength, patients with osteoporosis are at increased risk of osteoporotic fractures – the most severe complication of the disease. Osteoporotic fractures are caused by external trauma, like falls, which wouldn’t normally result in bone fractures in healthy individuals. These fractures present a major challenge; it is estimated that roughly one in three women and one in five men over the age of fifty years old will suffer from osteoporotic fractures. The treatment of osteoporotic fractures is usually surgery. However, Professor Jiacan Su and colleagues at the Shanghai University Institute of Translational Medicine, China, point out three common problems with current surgical approaches. Orthopaedic surgeons in China often have insufficient knowledge of osteoporosis, lack a thorough conception of the abnormal bone microenvironment in osteoporosis, and underestimate the effectiveness of bone grafting. Also, difficulties associated with fracture healing after surgery include delayed bone healing and secondary bone loss, as well as complications such as pneumonia, pressure ulcers, and thrombosis – which can be fatal. According to statistics, 21%–30% of elderly hip-fracture patients die within a year of injury.

Targeting L-plastin prevents pre-osteoclast fusion and promotes PDGF-BB secretion.

With such complications and poor prognosis, the research team propose a ‘three-in-one’ bone-repair strategy to prevent and treat osteoporosis. The research team have conducted substantial research in this field, publishing several articles on the pathogenesis of osteoporosis, potential therapies for bone loss and bone fracture healing. Building on their extensive existing research and more than 20 years of clinical experience, the researchers propose a new approach. The ‘three-in-one’ bone-repair strategy covers three main cores: treat osteoporosis, emphasise bone grafting, and accelerate fracture healing. They hope their new triumvirate approach will advance diagnosis and treatment to improve the quality of life and prognosis of patients.

“One in three women and one in five men over the age of fifty will experience osteoporotic fractures.”

Core 1: Treat osteoporosis
The researchers have conducted considerable research to understand the pathogenesis of osteoporosis and to explore potential therapies for bone loss. In a study investigating the actin-bundling protein, L-plastin (LPL), they demonstrated that oroxylin A (an LPL inhibitor) could speed up bone fracture healing and maintain bone mass in a mice model with induced osteoporosis. Their study, published in Science Advances, indicates that targeting LPL could be used as a therapy in disorders marked by bone loss. In diseases such as postmenopausal osteoporosis increased adipose tissue (fat) in bone marrow is associated with a higher risk of fractures. Receptor activator of nuclear factor-KB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of osteoclasts from white cells such as monocytes and macrophages. In another study, the researchers showed that deletion of RANKL in bone marrow adipose lineage cells resulted in decreased osteoclast formation and bone resorption. Thus, they suggest that targeting bone marrow adiposity could help prevent bone loss. This vital research into the pathogenies of osteoporosis has opened avenues for potential treatments warranting further exploration. Research for bone-specific treatments is ongoing to develop new effective therapies that could prevent and treat osteoporosis.

Receptor activator of nuclear factor-KB ligand (RANKL) signalling inhibits osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs).

Paving the way for the development of these much-needed new treatments, the researchers innovatively used nanomedicine to reverse age-related bone loss. Nanomedicine is the use of nanomaterials (exceedingly small particles) in the diagnosis, management, or treatment of diseases. In osteoporosis pathology, there is a shift in bone marrow mesenchymal stem cells (BMSCs) to favour the formation of adipocytes (adipogenesis), over-formation of bone causing increased adipocytes in the bone marrow, and poor bone formation. The micro-RNA MiR-188 regulates the differentiation of BMSCs, stimulating adipogenesis while inhibiting BMSC osteogenesis. Levels of MiR-188 increase with age, affecting bone formation in older individuals. Su and team used hybrid nanoparticles to deliver antagomir-188 (inhibitor of MiR-188) to the bone marrow of mice. This resulted in the inhibition of adipogenesis and the enhancement of osteogenesis of BMSCs, leading to a reversal of age-related bone loss. The study highlights the potential of such a nanoparticle delivery system as a future therapy to treat osteoporosis.

The advantages of tailored mesoporous nanocarriers.

“The ‘three-in-one’ bone-repair strategy covers three main cores: treat osteoporosis, emphasise bone grafting, and accelerate fracture healing.”

Core 2: Emphasise bone grafting
Bone grafting is transplanting bone tissue to aid bone repair. There is a high demand for bone grafting – bone is one of the most commonly transplanted tissues, second only to blood. Bone grafts may be autologous (bone taken from the patient themselves) or allogenic (taken from donors). However, both options have challenges. Synthetic bone grafts offer minimal risk and an affordable alternative but currently lack the bioactivity to aid in bone repair. In a review, the research team discuss the properties of drug-delivery systems (DDS) consisting of biomaterials used as nanocarriers and highlight their potential applications for the delivery of targeted therapy in diseases, including bone injury, to aid bone tissue regeneration. More research is needed as this interdisciplinary field evolves, but the team’s progress highlights its potential application for bone repair and bone regeneration. In another joint application of engineering and biomedical science, the researchers recently reviewed the concept of bone organoids and discussed construction options. Bone is one of the very few organs which can regenerate in adulthood, and bone organoids offer the possibility to study bone repair. Organoids are 3D systems built in vitro (in a laboratory) and have been developed to more closely replicate the physiological environment than cell culture and animal experiments. Bone organoids stem from human tissue and are self-renewing micro-bone tissues. Development is still in the initial stages but offers the promise of several potential applications, such as in the study of bone formation, for understanding disease mechanisms, and as a testbed for drug development.

The bone-targeted hybrid nanoparticle that promotes osteoclastogenesis and inhibits adipogenesis of BMSCs.

Core 3: Accelerate fracture healing
The final core of the ‘three-in-one’ bone-repair strategy is to accelerate fracture healing. Communication between osteoblasts and osteoclasts (the drivers that regulate bone formation and resorption) is essential for bone homeostasis (optimal functioning). Exosomes (a molecule containing extracellular vesicles within cells) play a vital role in this communication via the delivery of genetic codes. Exosomes have the potential for use in nanomedicine because of their low toxicity, small size, and structure which enables their surface to be modified for drug delivery and therapy. The researchers’ study aimed to determine if endothelial cell-secreted exosomes (EC-Exos) have a role in bone homeostasis and compare these exosomes with osteoblast-derived exosomes and bone marrow mesenchymal stem cell-derived exosomes. In comparison to osteoblast-derived exosomes and bone marrow mesenchymal stem cell-derived exosomes, the study demonstrated that EC-Exos have superior bone targeting. In vitro and in vivo studies showed EC-Exos can inhibit the formation of osteoclasts (osteoclastogenesis) and decrease bone resorption, aiding osteoporosis recovery by upregulating the micro-RNA, miRNA-155, in mice and mouse models. The study reveals the potential of EC-Exos as a nanomedicine to treat bone resorption disorders.

Bone marrow adipocyte-derived RANKL controls trabecular osteoclastogenesis.

Considering other aspects of fracture healing, Su and colleagues discuss and recommend the development and use of internal fixators to fix fractures. Furthermore, to accelerate fracture healing, the team recommends the benefits of using rehabilitation aids in perioperative exercises to help accelerate bone healing and aid recovery. This work offers valuable insights into treatments of osteoporosis and osteoporotic fractures, and new knowledge that is vital for the development of new, improved treatments. The diagnosis and treatment of osteoporotic fractures could be improved by focusing efforts and research on the three proposed core matters of the strategy. The researchers’ ‘three-in-one’ approach could lead to ‘better bone healing’ and therefore a ‘better life’ for patients with osteoporosis.

The potential applications of bone organoid.
What are the main advantages of your ‘three-in-one’ bone-repair strategy compared to existing approaches?
Firstly, osteoporotic fractures are different from common fractures and have their own characteristics. We systematically analysed this issue and considered the whole process of osteoporotic fracture. Secondly, previous strategies neglected the critical role of bone microenvironment and bone grafting in bone repair. Lastly, we value the essential function of basic research in promoting fracture healing. According to this strategy, we have performed many studies to explore the pathogenic mechanisms of osteoporosis, uncover targets to treat bone loss, and develop grafting biomaterials to promote fracture healing. Our ‘three-in-one’ bone-repair strategy reflects the consensus wisdom of experts and is very helpful to improve the clinical prognosis of patients with osteoporotic fractures.
How do you think nanomedicine will shape the future of treatment in your field?
Nanomedicine has substantial advantages to overcome the challenges in the field of bone repair. Firstly, the nanocarrier could achieve the targeted and controlled release of factors or drugs that promote fracture healing. Secondly, nano-scale scaffolds are ideal grafts to mimic natural bone, offering proper mechanical support and providing a suitable microenvironment for bone regeneration. Lastly, nanotechnology is very attractive for combating infection and the threat of bacterial resistance in trauma surgery. Although there is still a long way to go, nanomedicine looks promising to change the therapeutic algorithm of bone regeneration.

 

References

  • Chen, X, Hu, Y, Geng, Z, Su, J, (2022) The ‘three in one’ bone repair strategy for osteoporotic fractures. Frontiers in Endocrinology, doi.org/10.3389/fendo.2022.910602
  • Chen, S, Chen, X, Geng, Z, Su, J, (2022) The horizon of bone organoid: A perspective on construction and application. Bioactive Materials, 18, 15–25. doi.org/10.1016/j.bioactmat.2022.01.048
  • Hu, Y, Li, X, Zhi, X, et al (2021) RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss. EMBO reports, 22 (7), 1–14. doi.org/10.15252/embr.202152481
  • Hu, Y, Li, X, Zhang, Q, et al (2021) Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss. Bioactive Materials, 23;6 (9), 2905–13. doi.org/10.1016/j.bioactmat.2021.02.014
  • Li, X, Wang, L, Huang, B, et al (2020) Targeting actin-bundling protein L-plastin as an anabolic therapy for bone loss. Sci. Adv, 6 (47), 1–13. doi.org/10.1126/sciadv.abb7135
  • Song, H, Li, X, Zhao, Z, et al (2019) Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett, 19 (5), 3040–8. doi.org/10.1021/acs.nanolett.9b00287
DOI
10.26904/RF-142-2800316543

Research Objectives

Jiacan Su’s ‘three-in-one’ bone-repair strategy aims to treat osteoporosis, emphasise bone grafting, and accelerate fracture healing.

Funding

National Key Research and Development Plan (2018YFC2001500); National Natural Science Foundation of China (82172098, 81972254, 81871099, 32101084)

Collaborators

Xiao Chen, Yan Hu and Zhen Geng

Bio

Professsor Jiacan Su is the Dean of Shanghai University Institute of Translational Medicine and chief physician and professor of the department of orthopaedics trauma in Shanghai Changhai Hospital. His research interests focus on bone organoids, degenerative bone diseases, exosomes, the development and medical application of biomaterials, extracellular vesicles, tissue engineering, drug delivery, and stem cells.

Jiacan Su

Contact

Number 99 SHANGDA Road
Baoshan District, Shanghai
China

E: drsujiacan@163.com
T: +021 66132519
W: suitm.shu.edu.cn/info/1128/1283.htm

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