Characterization of OA development between sexes in the rat medial meniscal transection model

AbstractObjectiveOsteoarthritis (OA) is a chronic degenerative disease of the joints characterized by articular cartilage degradation. While there are clear sex differences in OA development in humans, most pre-clinical research has been conducted solely in male animals thus limiting the ability of these findings to be generalized to both sexes in the context of this disease. The objective of this study was to determine if sex impacts the progression and severity of OA in the rat medial meniscal tear (MMT) preclinical animal model used to surgically induce OA. It was hypothesized that differences would be observed between males and females following MMT surgery.DesignA MMT model was employed in male and female Lewis rats to induce OA. Animals were euthanized 3 weeks post-surgery and EPIC-μCT was used to quantitatively evaluate articular cartilage structure and composition, osteophyte volumes and subchondral bone structure.ResultsQuantitative analysis of the medial 1/3 articular cartilage via EPIC-μCT showed increased cartilage thickness and proteoglycan loss in the MMT of both sexes, when compared to sham. Additionally, both male and female animals in the MMT group had increased subchondral bone mineral density and larger total osteophyte volumes due to MMT.ConclusionThese data demonstrate that OA can be induced in both sexes using the rat MMT model. Moving forward, adding sex as a factor in preclinical OA studies should be standard practice in pre-clinical studies in order to elucidate more inclusive and translatable results into the clinic.

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Attenuation of Trauma-induced Osteoarthritis by Repetitive Intra-articular Administration of Peripheral Blood Derived Mesenchymal Stem Cells

10.21203/rs.3.rs-910616/v1 ◽

2021 ◽

Author(s):

Weiping Lin ◽

Zhengmeng Yang ◽

Liu Shi ◽

Haixing Wang ◽

Qi Pan ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Articular Cartilage ◽

Subchondral Bone ◽

Peripheral Blood ◽

Cartilage Degradation ◽

Cartilage Tissue ◽

Synovial Joint ◽

Post Surgery ◽

Sham Surgery

Abstract Background: Osteoarthritis (OA) is a chronic joint disease, characterized by articular cartilage degradation, subchondral bone hardening, and inflammation of the whole synovial joint. There is no pharmacological treatment in slowing down OA progression, leading to costly surgical interventions eventually. Cell therapy using chondrocytes or progenitor cells from different sources has been reported in clinical trials for OA management with some success, but outcomes are varied. Peripheral blood derived mesenchymal stem cells (PB-MSCs) are promising cells owing to their easy collection, superior migration, and differentiation potentials. In the current study, we evaluated the effect of intra-articular administration of PB-MSCs on the progression of OA in mice.Methods: C57BL/6J mice (8-10 weeks old male) were subjected to destabilization of the medial meniscus surgeries (DMM) on their right joints following protocols as previously reported. The mice after DMM were randomly treated with saline (vehicle control), PB-MSCs, or adipose tissue derived MSCs (AD-MSCs) (n = 7 per group). The mice treated with sham surgery were regarded as sham controls (n = 7). PB-MSCs and AD-MSCs were harvested and cultured according to previous published protocols, and pre-labeled with BrdU for 48 h before use. PB-MSCs or AD-MSCs (5 × 105 cells/mouse; passage 3~5) were injected into the right knee joints thrice post-surgery (except sham surgery group). The mice were euthanized at 8 weeks post-surgery and knee joint samples were collected for micro-CT and histological examinations.Results: PB-MSCs administration significantly reduced hardening of subchondral bone comparing to vehicle controls. Safranin O staining showed that PB-MSCs treatment ameliorated degeneration of articular cartilage, which is comparable to AD-MSCs treatment. The expression of catabolic marker MMP13 was significantly reduced in articular cartilage of PB-MSCs-treated groups comparing to vehicle controls. Co-expression of BrdU and Sox9 were detected, indicating injected PB-MSCs differentiated towards chondrocytes in situ. Reduced level of IL-6 in the peripheral sera of PB-MSCs- and AD-MSCs-treated mice was also determined. Conclusions: Repetitive administration of PB-MSCs or AD-MSCs halted OA progression through inhibiting cartilage degradation and inflammation. PB-MSCs may become a promising cell source for cartilage tissue repair and alleviation of OA progression.

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Osteoarthritis Early-, Mid- and Late-Stage Progression in the Rat Medial Meniscus Transection Model

10.1101/2021.03.11.434909 ◽

2021 ◽

Author(s):

Thanh N. Doan ◽

Jay M. McKinney ◽

Krishna A Pucha ◽

Fabrice C. Bernard ◽

Nick J. Willett

Keyword(s):

Articular Cartilage ◽

Disease Progression ◽

Subchondral Bone ◽

Late Stage ◽

Medial Meniscus ◽

Cartilage Damage ◽

Cartilage Degradation ◽

Cell Therapies ◽

Post Surgery ◽

Established Disease

AbstractOsteoarthritis is a degenerative disease of synovial joints affecting all tissues, including the articular cartilage and underlying subchondral bone. Osteoarthritis animal models can recapitulate aspects of human disease progression and are commonly used to test the development of drugs, biomaterials, and cell therapies for treatment. The rat medial meniscus transection (MMT) model is a surgically induced post-traumatic osteoarthritis model and is one of the most commonly used models for therapeutic development; however, it is typically used to evaluate the efficacy of therapies to prevent disease development rather than testing the treatment of disease progression in already established disease. We describe herein, the qualitative and quantitative changes to articular cartilage, subchondral bone, and formation of osteophytes in rats at early-(3-weeks post-surgery), mid-(6-weeks post-surgery) and late-(12-weeks post-surgery) stages of osteoarthritis progression. Tibiae of MMT-operated animals showed loss of proteoglycan and fibrillation formation on articular cartilage surfaces as early as 3-weeks post-surgery. Using a contrast-enhanced μCT technique, quantitative, 3-dimensional analysis of the tibiae showed that the articular cartilage initially thickened at 3- and 6-weeks post-surgery and then decreased at 12-weeks post-surgery. This decrease in cartilage thickness corresponded with increased lesions in the articular cartilage, including fully degraded surfaces down to the subchondral bone layer. In this rat MMT model, subchondral bone thickening was significant at 6-weeks post-surgery and seem to follow cartilage damage. Osteophytes were found at 3-weeks post-surgery, which coincided with articular cartilage degradation. Cartilaginous osteophytes preceded mineralization suggesting that these marginal tissue growths most likely occurred through endochondral ossification. The use of the rat MMT model has predominantly been used out to 3-weeks, and most studies determine the effect of therapies to delay or prevent the onset of osteoarthritis. We provide evidence that an extension of the rat MMT model out to 6 and 12 weeks resembled more severe phenotypes of human osteoarthritis. The mid- to late-stages of rat MMT model can be used to evaluate the therapeutic efficacy of novel treatments to treat the progression of established disease — since patients typically present in the clinic when the disease is established and becomes symptomatic, thus evaluating the efficacy of new treatments at the late stage will be important for eventual clinical translation.

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Arthroscopic Articular Cartilage Scores of the Canine Stifle Joint with Naturally Occurring Cranial Cruciate Ligament Disease

Veterinary and Comparative Orthopaedics and Traumatology ◽

10.1055/s-0040-1719064 ◽

2020 ◽

Author(s):

Kimberly A. Agnello ◽

Kei Hayashi ◽

Dorothy Cimino Brown

Keyword(s):

Articular Cartilage ◽

Cruciate Ligament ◽

Cartilage Damage ◽

Meniscal Tear ◽

Trochlear Groove ◽

Cranial Cruciate Ligament ◽

Stifle Joint ◽

Naturally Occurring ◽

Medial Meniscal Tear ◽

Severity Scores

Abstract Objective This study aimed to evaluate frequency, location and severity of cartilage pathology in dogs with naturally occurring cranial cruciate ligament (CCL) disease. Study Design Stifle arthroscopic video recordings (n = 120) were reviewed. A modified Outerbridge classification system (MOCS) (0–4) was used to score cartilage at 10 locations in the femorotibial (medial and lateral femoral condyles and tibial plateaus) and patellofemoral compartments (proximal, middle and distal locations of the patella and femoral trochlear groove) of the stifle joint. Synovial pathology was scored and the presence of a medial meniscal tear was recorded. A Kruskal–Wallis test was used to evaluate association of location and synovitis with cartilage score; and presence of meniscal tear with cartilage and synovitis scores. Bonferroni correction was utilized and p < 0.05 was considered significant. Results Cartilage pathology and synovitis were identified in all joints. Overall cartilage severity scores were low (median MOCS 1). The median MOCS of the proximal trochlear groove (2) was significantly higher than all other locations evaluated. Higher synovitis scores were significantly associated with higher cartilage severity scores and a medial meniscal tear had no association with cartilage severity scores or synovitis. Conclusion Arthroscopic articular cartilage lesions are common in dogs with CCL disease at the time of surgical intervention, although the severity of cartilage damage is mild. The proximal trochlear groove of the femur had the most severe cartilage score in the stifle joint.

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Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis

Cells ◽

10.3390/cells9040927 ◽

2020 ◽

Vol 9 (4) ◽

pp. 927 ◽

Cited By ~ 5

Author(s):

Szu-Yu Chien ◽

Chun-Hao Tsai ◽

Shan-Chi Liu ◽

Chien-Chung Huang ◽

Tzu-Hung Lin ◽

...

Keyword(s):

Articular Cartilage ◽

Signaling Pathways ◽

Bone Remodeling ◽

Subchondral Bone ◽

Bone Destruction ◽

Cartilage Degeneration ◽

Cartilage Degradation ◽

Mitogen Activated Protein Kinase ◽

Bone Morphogenetic Protein 2 ◽

Joint Disease

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

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Characterization of human cancellous and subchondral bone with respect to electro physical properties and bone mineral density by means of impedance spectroscopy

Medical Engineering & Physics ◽

10.1016/j.medengphy.2017.04.002 ◽

2017 ◽

Vol 45 ◽

pp. 34-41 ◽

Cited By ~ 6

Author(s):

Yvonne Haba ◽

Andreas Wurm ◽

Martin Köckerling ◽

Christoph Schick ◽

Wolfram Mittelmeier ◽

...

Keyword(s):

Bone Mineral Density ◽

Impedance Spectroscopy ◽

Physical Properties ◽

Bone Mineral ◽

Subchondral Bone ◽

Mineral Density

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Early Alterations of Subchondral Bone in the Rat Anterior Cruciate Ligament Transection Model of Osteoarthritis

Cartilage ◽

10.1177/1947603519878479 ◽

2019 ◽

pp. 194760351987847 ◽

Cited By ~ 2

Author(s):

Nik Aizah ◽

Pan Pan Chong ◽

Tunku Kamarul

Keyword(s):

Anterior Cruciate Ligament ◽

Articular Cartilage ◽

Subchondral Bone ◽

Cruciate Ligament ◽

Quantitative Computed Tomography ◽

Cartilage Loss ◽

Control Group ◽

Mineral Density ◽

Anterior Cruciate Ligament Transection ◽

Anterior Cruciate

Objective Advances in research have shown that the subchondral bone plays an important role in the propagation of cartilage loss and progression of osteoarthritis (OA), but whether the subchondral bone changes precede or lead to articular cartilage loss remains debatable. In order to elucidate the subchondral bone and cartilage changes that occur in early OA, an experiment using anterior cruciate ligament transection (ACLT) induced posttraumatic OA model of the rat knee was conducted. Design Forty-two Sprague Dawley rats were divided into 2 groups: the ACLT group and the nonoperated control group. Surgery was conducted on the ACLT group, and subsequently rats from both groups were sacrificed at 1, 2, and 3 weeks postsurgery. Subchondral bone was evaluated using a high-resolution peripheral quantitative computed tomography scanner, while cartilage was histologically evaluated and scored. Results A significant reduction in the subchondral trabecular bone thickness and spacing was found as early as 1 week postsurgery in ACLT rats compared with the nonoperated control. This was subsequently followed by a reduction in bone mineral density and bone fractional volume at week 2, and finally a decrease in the trabecular number at week 3. These changes occurred together with cartilage degeneration as reflected by an increasing Mankin score over all 3 weeks. Conclusions Significant changes in subchondral bone occur very early in OA concurrent with surface articular cartilage degenerative change suggest that factors affecting bone remodeling and resorption together with cartilage matrix degradation occur very early in the disease.

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Characterization of Subchondral Bone Repair for Marrow-Stimulated Chondral Defects and Its Relationship to Articular Cartilage Resurfacing

The American Journal of Sports Medicine ◽

10.1177/0363546511403282 ◽

2011 ◽

Vol 39 (8) ◽

pp. 1731-1741 ◽

Cited By ~ 76

Author(s):

Hongmei Chen ◽

Anik Chevrier ◽

Caroline D. Hoemann ◽

Jun Sun ◽

Wei Ouyang ◽

...

Keyword(s):

Articular Cartilage ◽

Subchondral Bone ◽

Bone Repair ◽

Chondral Defects

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Trabecular and cortical bone are unaltered in response to chronic lipopolysaccharide exposure via osmotic pumps in male and female CD-1 mice

PLoS ONE ◽

10.1371/journal.pone.0243933 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0243933

Author(s):

Kirsten N. Bott ◽

Jenalyn L. Yumol ◽

Elena M. Comelli ◽

Panagiota Klentrou ◽

Sandra J. Peters ◽

...

Keyword(s):

Cortical Bone ◽

Bone Structure ◽

Low Grade ◽

Micro Computed Tomography ◽

Mineral Density ◽

Potent Inducer ◽

Male And Female ◽

Osmotic Pumps ◽

Longitudinal Response

Chronic low-grade inflammation has been identified as an underlying cause of many diseases including osteoporosis. Lipopolysaccharide (LPS) is a potent inducer of the inflammatory response that can negatively affect bone outcomes by upregulating bone resorption and inhibiting bone formation. The objective of this study was to assess the longitudinal response of trabecular and cortical bone structure and bone mineral density to LPS continuously administered for 12 weeks in male and female CD-1 mice. Mice were assigned to one of four LPS groups at 8-weeks of age: placebo (0.0 μg/d), low (0.9 μg/d), mid (3.6 μg/d) and high (14.4 μg/d) dose. Trabecular and cortical bone outcomes were measured at 8, 12, 16, and 20 weeks of age using in vivo micro-computed tomography. The anticipated serum LPS dose-dependent response was not observed. Therefore, the low, mid, and high LPS groups were combined for analysis. Compared to the placebo group, endpoint serum LPS was elevated in both males (p < 0.05) and females (p < 0.05) when all LPS treatment groups were combined. However, there was no significant change in trabecular or cortical bone outcomes in the combined LPS groups compared to the placebo following the 12-week LPS intervention for either sex. This suggests that although serum LPS was elevated following the 12-week LPS intervention, the dosages administered using the osmotic pumps was not sufficient to negatively impact trabecular or cortical bone outcomes in either male or female CD-1 mice.

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