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Bone & Joint Research
Vol. 7, Issue 10 | Pages 548 - 560
1 Oct 2018
Qayoom I Raina DB Širka A Tarasevičius Š Tägil M Kumar A Lidgren L

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions. Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2


Bone & Joint Research
Vol. 12, Issue 11 | Pages 677 - 690
1 Nov 2023
Wang X Jiang W Pan K Tao L Zhu Y

Aims

Currently, the effect of drug treatment for osteoporosis is relatively poor, and the side effects are numerous and serious. Melatonin is a potential drug to improve bone mass in postmenopausal women. Unfortunately, the mechanism by which melatonin improves bone metabolism remains unclear. The aim of this study was to further investigate the potential mechanism of melatonin in the treatment of osteoporosis.

Methods

The effects of melatonin on mitochondrial apoptosis protein, bmal1 gene, and related pathway proteins of RAW264.7 (mouse mononuclear macrophage leukaemia cells) were analyzed by western blot. Cell Counting Kit-8 was used to evaluate the effect of melatonin on cell viability. Flow cytometry was used to evaluate the effect of melatonin on the apoptosis of RAW264.7 cells and mitochondrial membrane potential. A reactive oxygen species (ROS) detection kit was used to evaluate the level of ROS in osteoclast precursors. We used bmal1-small interfering RNAs (siRNAs) to downregulate the Bmal1 gene. We established a postmenopausal mouse model and verified the effect of melatonin on the bone mass of postmenopausal osteoporosis in mice via micro-CT. Bmal1 lentiviral activation particles were used to establish an in vitro model of overexpression of the bmal1 gene.


Bone & Joint Research
Vol. 12, Issue 6 | Pages 375 - 386
12 Jun 2023
Li Z

Aims

Long non-coding RNAs (lncRNAs) act as crucial regulators in osteoporosis (OP). Nonetheless, the effects and potential molecular mechanism of lncRNA PCBP1 Antisense RNA 1 (PCBP1-AS1) on OP remain largely unclear. The aim of this study was to explore the role of lncRNA PCBP1-AS1 in the pathogenesis of OP.

Methods

Using quantitative real-time polymerase chain reaction (qRT-PCR), osteogenesis-related genes (alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN), and Runt-related transcription factor 2 (RUNX2)), PCBP1-AS1, microRNA (miR)-126-5p, group I Pak family member p21-activated kinase 2 (PAK2), and their relative expression levels were determined. Western blotting was used to examine the expression of PAK2 protein. Cell Counting Kit-8 (CCK-8) assay was used to measure cell proliferation. To examine the osteogenic differentiation, Alizarin red along with ALP staining was used. RNA immunoprecipitation assay and bioinformatics analysis, as well as a dual-luciferase reporter, were used to study the association between PCBP1-AS1, PAK2, and miR-126-5p.


Bone & Joint Research
Vol. 12, Issue 3 | Pages 219 - 230
10 Mar 2023
Wang L Li S Xiao H Zhang T Liu Y Hu J Xu D Lu H

Aims

It has been established that mechanical stimulation benefits tendon-bone (T-B) healing, and macrophage phenotype can be regulated by mechanical cues; moreover, the interaction between macrophages and mesenchymal stem cells (MSCs) plays a fundamental role in tissue repair. This study aimed to investigate the role of macrophage-mediated MSC chondrogenesis in load-induced T-B healing in depth.

Methods

C57BL/6 mice rotator cuff (RC) repair model was established to explore the effects of mechanical stimulation on macrophage polarization, transforming growth factor (TGF)-β1 generation, and MSC chondrogenesis within T-B enthesis by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Macrophage depletion was performed by clodronate liposomes, and T-B healing quality was evaluated by histology and biomechanics. In vitro, bone marrow-derived macrophages (BMDMs) were stretched with CELLOAD-300 load system and macrophage polarization was identified by flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). MSC chondrogenic differentiation was measured by histochemical analysis and qRT-PCR. ELISA and qRT-PCR were performed to screen the candidate molecules that mediated the pro-chondrogenic function of mechanical stimulated BMDMs.


Bone & Joint Research
Vol. 13, Issue 2 | Pages 52 - 65
1 Feb 2024
Yao C Sun J Luo W Chen H Chen T Chen C Zhang B Zhang Y

Aims

To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism.

Methods

In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed.


Aims

This study examined the relationship between obesity (OB) and osteoporosis (OP), aiming to identify shared genetic markers and molecular mechanisms to facilitate the development of therapies that target both conditions simultaneously.

Methods

Using weighted gene co-expression network analysis (WGCNA), we analyzed datasets from the Gene Expression Omnibus (GEO) database to identify co-expressed gene modules in OB and OP. These modules underwent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interaction analysis to discover Hub genes. Machine learning refined the gene selection, with further validation using additional datasets. Single-cell analysis emphasized specific cell subpopulations, and enzyme-linked immunosorbent assay (ELISA), protein blotting, and cellular staining were used to investigate key genes.


Bone & Joint Research
Vol. 10, Issue 8 | Pages 488 - 497
10 Aug 2021
Cleemann R Sorensen M West A Soballe K Bechtold JE Baas J

Aims

We wanted to evaluate the effects of a bone anabolic agent (bone morphogenetic protein 2 (BMP-2)) on an anti-catabolic background (systemic or local zoledronate) on fixation of allografted revision implants.

Methods

An established allografted revision protocol was implemented bilaterally into the stifle joints of 24 canines. At revision surgery, each animal received one BMP-2 (5 µg) functionalized implant, and one raw implant. One group (12 animals) received bone graft impregnated with zoledronate (0.005 mg/ml) before impaction. The other group (12 animals) received untreated bone graft and systemic zoledronate (0.1 mg/kg) ten and 20 days after revision surgery. Animals were observed for an additional four weeks before euthanasia.


Bone & Joint Research
Vol. 11, Issue 5 | Pages 260 - 269
3 May 2022
Staats K Sosa BR Kuyl E Niu Y Suhardi V Turajane K Windhager R Greenblatt MB Ivashkiv L Bostrom MPG Yang X

Aims

To develop an early implant instability murine model and explore the use of intermittent parathyroid hormone (iPTH) treatment for initially unstable implants.

Methods

3D-printed titanium implants were inserted into an oversized drill-hole in the tibiae of C57Bl/6 mice (n = 54). After implantation, the mice were randomly divided into three treatment groups (phosphate buffered saline (PBS)-control, iPTH, and delayed iPTH). Radiological analysis, micro-CT (µCT), and biomechanical pull-out testing were performed to assess implant loosening, bone formation, and osseointegration. Peri-implant tissue formation and cellular composition were evaluated by histology.


Bone & Joint Research
Vol. 11, Issue 5 | Pages 304 - 316
17 May 2022
Kim MH Choi LY Chung JY Kim E Yang WM

Aims

The association of auraptene (AUR), a 7-geranyloxycoumarin, on osteoporosis and its potential pathway was predicted by network pharmacology and confirmed in experimental osteoporotic mice.

Methods

The network of AUR was constructed and a potential pathway predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms enrichment. Female ovariectomized (OVX) Institute of Cancer Research mice were intraperitoneally injected with 0.01, 0.1, and 1 mM AUR for four weeks. The bone mineral density (BMD) level was measured by dual-energy X-ray absorptiometry. The bone microstructure was determined by histomorphological changes in the femora. In addition, biochemical analysis of the serum and assessment of the messenger RNA (mRNA) levels of osteoclastic markers were performed.


Bone & Joint Research
Vol. 10, Issue 12 | Pages 820 - 829
15 Dec 2021
Schmidutz F Schopf C Yan SG Ahrend M Ihle C Sprecher C

Aims

The distal radius is a major site of osteoporotic bone loss resulting in a high risk of fragility fracture. This study evaluated the capability of a cortical index (CI) at the distal radius to predict the local bone mineral density (BMD).

Methods

A total of 54 human cadaver forearms (ten singles, 22 pairs) (19 to 90 years) were systematically assessed by clinical radiograph (XR), dual-energy X-ray absorptiometry (DXA), CT, as well as high-resolution peripheral quantitative CT (HR-pQCT). Cortical bone thickness (CBT) of the distal radius was measured on XR and CT scans, and two cortical indices mean average (CBTavg) and gauge (CBTg) were determined. These cortical indices were compared to the BMD of the distal radius determined by DXA (areal BMD (aBMD)) and HR-pQCT (volumetric BMD (vBMD)). Pearson correlation coefficient (r) and intraclass correlation coefficient (ICC) were used to compare the results and degree of reliability.


Bone & Joint Research
Vol. 9, Issue 10 | Pages 709 - 718
1 Oct 2020
Raina DB Liu Y Jacobson OLP Tanner KE Tägil M Lidgren L

Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health.

Cite this article: Bone Joint Res 2020;9(10):709–718.


Bone & Joint Research
Vol. 9, Issue 8 | Pages 524 - 530
1 Aug 2020
Li S Mao Y Zhou F Yang H Shi Q Meng B

Osteoporosis (OP) is a chronic metabolic bone disease characterized by the decrease of bone tissue per unit volume under the combined action of genetic and environmental factors, which leads to the decrease of bone strength, makes the bone brittle, and raises the possibility of bone fracture. However, the exact mechanism that determines the progression of OP remains to be underlined. There are hundreds of trillions of symbiotic bacteria living in the human gut, which have a mutually beneficial symbiotic relationship with the human body that helps to maintain human health. With the development of modern high-throughput sequencing (HTS) platforms, there has been growing evidence that the gut microbiome may play an important role in the programming of bone metabolism. In the present review, we discuss the potential mechanisms of the gut microbiome in the development of OP, such as alterations of bone metabolism, bone mineral absorption, and immune regulation. The potential of gut microbiome-targeted strategies in the prevention and treatment of OP was also evaluated.

Cite this article: Bone Joint Res 2020;9(8):524–530.


Bone & Joint Research
Vol. 7, Issue 6 | Pages 406 - 413
1 Jun 2018
Shabestari M Kise NJ Landin MA Sesseng S Hellund JC Reseland JE Eriksen EF Haugen IK

Objectives

Little is known about tissue changes underlying bone marrow lesions (BMLs) in non-weight-bearing joints with osteoarthritis (OA). Our aim was to characterize BMLs in OA of the hand using dynamic histomorphometry. We therefore quantified bone turnover and angiogenesis in subchondral bone at the base of the thumb, and compared the findings with control bone from hip OA.

Methods

Patients with OA at the base of the thumb, or the hip, underwent preoperative MRI to assess BMLs, and tetracycline labelling to determine bone turnover. Three groups were compared: trapezium bones removed by trapeziectomy from patients with thumb base OA (n = 20); femoral heads with (n = 24); and those without (n = 9) BMLs obtained from patients with hip OA who underwent total hip arthroplasty.