The in Vivo Effect of Prophylactic Subchondral Bone Protection of Osteoarthritic Synovial Membrane in Bone-Specific Ephb4–Overexpressing Mice

Authors

Gladys Valverde-Franco, David Hum, Koichi Matsuo, Bertrand Lussier, Jean-Pierre Pelletier, Hassan Fahmi, Mohit Kapoor, Johanne Martel-Pelletier

Abstract

Osteoarthritis (OA) is characterized by progressive joint destruction, including synovial membrane alteration. EphB4 and its ligand ephrin-B2 were found in vitro to positively affect OA subchondral bone and cartilage. In vivo in an experimental mouse model overexpressing bone-specific Ephb4 (TgEphB4), a protective effect was found on both the subchondral bone and cartilage during OA. We investigated in the TgEphB4 mouse model the in vivo effect on synovial membrane during OA. Knee OA was surgically induced by destabilization of the medial meniscus (DMM). Synovial membrane was evaluated using histology, histomorphometry, IHC, and real-time PCR. DMM-TgEphB4 mice had a significant decrease in synovial membrane thickness, vascular endothelial growth factor, and the profibrotic markers fibrin, type 1 procollagen, type 3 collagen, connective tissue growth factor, smooth muscle actin-α, cartilage oligomeric matrix protein, and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 compared with DMM–wild-type (WT) mice. Moreover, factors known to modulate transforming growth factor-β signaling, transforming growth factor receptor 1/ALK1, phosphorylated Smad-1, and heat shock protein 90β were significantly decreased in DMM-TgEphB4 compared with DMM-WT mice. Ephb4 overexpression also exhibited a protective effect on synovial membrane thickness of aged (24-month-old) mice. Overexpression of bone-specific Ephb4 clearly demonstrated prevention of the development and/or progression of fibrosis in OA synovial membrane, reinforcing the hypothesis that protecting the subchondral bone prophylactically and during OA reduces the pathologic changes in other articular tissues.

Link To Article

http://dx.doi.org/10.1016/j.ajpath.2014.10.004

Identical subchondral bone microarchitecture pattern with increased bone reporption observed in rheumatoid arthritis as compared to osteoarthritis

Authors

Guangyi Li, Yuanchen Ma, Tak S. Cheng, Euphemie Landao-Bassonga, An Qin, Nathan J. Pavlos, Changqing Zhang, Qiujian Zheng, Ming H. Zheng

Abstract

Objectives To analyze the differences in microarchitecture and bone remodeling of subchondral bone in femoral heads from patients with rheumatoid arthritis (RA) and osteoarthritis (OA).

Designs Peri-articualr bone samples, including subchondral trabecular bone (STB) and deeper trabecular bone (DTB) were extracted from the load-bearing region of femoral heads from 20 patients with RA and 40 patients with OA during hip replacement surgery. Micro-CT, histomorphometry and backscatter scanning electron microscopy were performed to assess microarchitecture and bone histology parameters.

Results In both RA and OA, STB showed more sclerotic microarchitecture and more active bone remodeling, compared to DTB. RA and OA showed similar microarchitecture characteristics in both STB and DTB, despite STB in RA exhibiting higher bone resorption. In addition, there was no difference in the frequency of bone cysts in STB between RA and OA. In STB, the trabecular bone surrounding subchondral bone cysts (Cys-Tb) was more sclerotic than the trabecular bone found distant to cysts (Peri-Tb), with a higher level of bone remodeling. Both Cys-Tb region and Peri-Tb region were detected to have similar microarchitectural and bone remodeling characteristics in RA and OA.

Conclusions Apart from higher bone resorption in the general subchondral bone of RA samples, the peri-articular bone exhibited similar microarchitectural and bone remodeling characteristics in RA and OA.

Link To Article

http://dx.doi.org/10.1016/j.joca.2014.08.015

A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor...

Title

A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor PD0325901 Increases Bone Formation in a Murine Model of Neurofibromatosis Type I Pseudarthrosis

Authors

J. El-Hoss, PhD; T. Cheng, BE/BMedSc; E.C. Carpenter, MRCS; K. Sullivan, PhD; N. Deo, BSc(Hons); K. Mikulec ; D.G. Little, MBBS, FRACS(Orth), PhD; A. Schindeler, PhD

Abstract

Background: Congenital tibial dysplasia is a severe pediatric condition that classically results in a persistent pseudarthrosis. A majority of these cases are associated with neurofibromatosis type I (NF1), a genetic disorder in which inactivation of the NF1 gene leads to overactivity of the Ras-MEK-MAPK (mitogen-activated protein kinase) signaling pathway. We therefore hypothesized that pharmaceutical inhibition of MEK-MAPK may be a beneficial therapeutic strategy.

Methods: In vitro methods were used to demonstrate a role for the MEK inhibitor PD0325901 in promoting osteogenic differentiation in Nf1−/− calvarial osteoblasts. Local applications of rhBMP-2 and/or PD0325901 were then tested in a mouse model of NF1 tibial pseudarthrosis featuring localized double inactivation of the Nf1 gene in a fracture. Mice received no treatment, PD0325901 (10 mg/kg/day from two days before fracture to ten days after fracture), rhBMP-2 (10 μg), or a combination of rhBMP-2 and PD0325901.

Results: Animals treated with the delivery vehicle alone, PD0325901, rhBMP-2, or the PD0325901 + rhBMP-2 combination showed union rates of 0%, 8%, 69% (p < 0.01), or 80% (p < 0.01), respectively, at twenty-one days after fracture. Mice treated with the rhBMP-2 + PD0325901 combination displayed a callus volume sixfold greater than the vehicle controls and twofold greater than the group receiving rhBMP-2 alone. Although MEK inhibition combined with rhBMP-2 led to increases in bone formation and union, the proportion of fibrous tissue in the callus was not significantly reduced.

Conclusions: The data suggest that MEK inhibition can promote bone formation in combination with rhBMP-2 in the context of an NF1 pseudarthrosis. However, PD0325901 did not promote substantive bone anabolism in the absence of an exogenous anabolic stimulus and did not suppress fibrosis.

Clinical Relevance: This study examines a signaling pathway-based approach to treating poor bone healing in a model of NF1 pseudarthrosis.

Link To Article

http://dx.doi.org/10.2106/JBJS.M.00862

Hip osteoarthritis and osteoporosis: clinical and histomorphometric considerations

Authors

Umberto Tarantino, Monica Celi, Cecilia Rao, Maurizio Feola, Irene Cerocchi, Elena Gasbarra, Amedeo Ferlosio and Augusto Orlandi

Abstract

Although an inverse relationship between osteoarthritis (OA) and osteoporosis (OP) has been shown by some studies, other reports supported their co-existence. To clarify this relationship we analyzed the interplay between clinical and histomorphometric features. Bone mineral density (BMD) and histomorphometric structure were assessed in 80 patients of four different age-matched groups undergoing hip arthroplasty for severe OA or OP-related femoral fracture. Harris Hip Score was also performed. Surgical double osteotomy of the femoral head was performed and microscopic bone slice samples analysis was performed by using a BioQuant Osteo software. Bone volume fraction (BV/TV) was lower (p<0.01) in subjects with femoral neck fracture (20.77±4.34%) than in subjects with non-osteopenic OA (36.49±7.73%) or osteopenic OA (32.93±6.83%), whereas no difference was detected between subjects with femoral neck fractures and those with combined OA and OP (20.71±5.23%). Worse Harris Hip Score was found in those patients with the lowest BMD and BV/TV values. Our data support recent evidences indicating the possibility of impaired bone volume fraction in OA patients, with a high risk of developing OP, likely for their decreased mobility. Further studies are needed in order to investigate biomolecular pathway and/or growth factors involved in bone volume impairment in OA patients.

Link To Article

http://downloads.hindawi.com/journals/ije/aip/372021.pdf

Deleterious effects of osteoarthritis on the structure and function of the meniscal enthesis

Authors

Adam C. Abraham, Hannah M. Pauly, Tammy L. Haut Donahue

Abstract

Objective

The ability of menisci to prevent osteoarthritis (OA) is dependent on the integrity of the complex meniscal entheses, the attachments of the menisci to the underlying subchondral bone. The goal of this study was to determine mechanical and structural changes in meniscal entheses after the onset of osteoarthritis.

Design

Healthy and osteoarthritic meniscal entheses were evaluated for changes in histomorphological characteristics, mineralization, and mechanical properties. GAG and calcium in the insertion were evaluated with histological staining techniques. The extent of calcium deposition was assessed and tidemark integrity was quantified. Changes in the mineralized zone of the insertion was examined using micro-computed tomography to determine bone mineral density, cortical zone thickness, and mineralization gradient. Mechanical properties of the entheses were measured using nanoindentation techniques to obtain material properties based on viscoelastic analysis.

Results

GAG thickness in the calcified fibrocartilage zone and calcium content were significantly greater in osteoarthritic anterior meniscal entheses. Tidemark integrity was significantly decreased in OA tissue, particularly in the medial anterior enthesis. The mineralized zone of osteoarthritic meniscal entheses was significantly thicker than in healthy entheses and showed decreased bone mineral density. Fitting of mineralization data to a sigmoidal Gompertz function revealed a lower rate of increase in mineralization in osteoarthritic tissue. Analysis of viscoelastic mechanical properties revealed increased compliance in osteoarthritic tissue.

Conclusions

These data suggest that significant changes occur at meniscal enthesis sites with the onset of osteoarthritis. Mechanical and structural changes in meniscal entheses may contribute to meniscal extrusion, which has been show to increase the progression of OA.

Link To Article

http://dx.doi.org/10.1016/j.joca.2013.11.013

The Inhibition of Subchondral Bone Lesions Significantly Reversed the Weight-Bearing Deficit and the Overexpression of CGRP in...

Title

The Inhibition of Subchondral Bone Lesions Significantly Reversed the Weight-Bearing Deficit and the Overexpression of CGRP in DRG Neurons, GFAP and Iba-1 in the Spinal Dorsal Horn in the Monosodium Iodoacetate Induced Model of Osteoarthritis Pain

Authors

Degang Yu, Fengxiang Liu, Ming Liu, Xin Zhao, Xiaoqing Wang, Yang Li, Yuanqing Mao, Zhenan Zhu

Abstract

Background

Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA). Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain.

Methods

Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA) into the rat knee joint. Zoledronic acid (ZOL), a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG), and spinal glial activation status using glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling.

Results

MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected.

Conclusions

The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.

Link to Article

http://dx.doi.org/10.1371/journal.pone.0077824