Less mechanical loading attenuates osteoarthritis by reducing cartilage degeneration, subchondral bone remodelling, secondary inflammation, and activation of NLRP3 inflammasome

Aims Osteoarthritis (OA) is a disabling joint disorder and mechanical loading is an important pathogenesis. This study aims to investigate the benefits of less mechanical loading created by intermittent tail suspension for knee OA. Methods A post-traumatic OA model was established in 20 rats (12 weeks old, male). Ten rats were treated with less mechanical loading through intermittent tail suspension, while another ten rats were treated with normal mechanical loading. Cartilage damage was determined by gross appearance, Safranin O/Fast Green staining, and immunohistochemistry examinations. Subchondral bone changes were analyzed by micro-CT and tartrate-resistant acid phosphatase (TRAP) staining, and serum inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA). Results Our radiographs showed that joint space was significantly enlarged in rats with less mechanical loading. Moreover, cartilage destruction was attenuated in the less mechanical loading group with lower histological damage scores, and lower expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, matrix metalloproteinase (MMP)-3, and MMP-13. In addition, subchondral bone abnormal changes were ameliorated in OA rats with less mechanical loading, as reduced bone mineral density (BMD), bone volume/tissue volume (BV/TV), and number of osteophytes and osteoclasts in the subchondral bone were observed. Finally, the level of serum inflammatory cytokines was significantly downregulated in the less mechanical loading group compared with the normal mechanical loading group, as well as the expression of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), caspase-1, and interleukin 1β (IL-1β) in the cartilage. Conclusion Less mechanical loading alleviates cartilage destruction, subchondral bone changes, and secondary inflammation in OA joints. This study provides fundamental insights into the benefit of non-weight loading rest for patients with OA. Cite this article: Bone Joint Res 2020;9(10):731–741.

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Do Subchondral Bone Changes Exacerbate or Precede Articular Cartilage Destruction in Osteoarthritis of the Elderly?

Gerontology ◽

10.1159/000213866 ◽

1997 ◽

Vol 43 (5) ◽

pp. 296-304 ◽

Cited By ~ 92

Author(s):

Allen J. Bailey ◽

Jason P. Mansell

Keyword(s):

Articular Cartilage ◽

Subchondral Bone ◽

The Elderly ◽

Cartilage Destruction ◽

Bone Changes

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Undenatured Type II Collagen Relieves Bone Impairment through Improving Inflammation and Oxidative Stress in Ageing db/db Mice

Molecules ◽

10.3390/molecules26164942 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4942

Author(s):

Rui Fan ◽

Yuntao Hao ◽

Xinran Liu ◽

Jiawei Kang ◽

Jiani Hu ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Cytokines ◽

Intervention Group ◽

Type Ii Collagen ◽

Tartrate Resistant Acid Phosphatase ◽

Type Ii ◽

Mineral Density ◽

Ageing Model ◽

And Oxidative Stress ◽

Undenatured Type Ii Collagen

Ageing-related bone impairment due to exposure to hyperglycemic environment is scarcely researched. The aim was to confirm the improvement effects of undenatured type II collagen (UC II) on bone impairment in ageing db/db mice, and the ageing model was established by normal feeding for 48-week-old. Then, the ageing db/db mice were randomly assigned to UC II intervention, the ageing model, and the chondroitin sulfate + glucosamine hydrochloride control groups. After 12 weeks of treatment, femoral microarchitecture and biomechanical parameters were observed, biomarkers including bone metabolism, inflammatory cytokines, and oxidative stress were measured, and the gastrocnemius function and expressions of interleukin (IL) 1β, receptor activator of nuclear factor (NF)-κB ligand (RANKL), and tartrate-resistant acid phosphatase (TRAP) were analyzed. The results showed that the mice in the UC II intervention group showed significantly superior bone and gastrocnemius properties than those in the ageing model group, including bone mineral density (287.65 ± 72.77 vs. 186.97 ± 32.2 mg/cm3), gastrocnemius index (0.46 ± 0.07 vs. 0.18 ± 0.01%), muscle fiber diameter (0.0415 ± 0.005 vs. 0.0330 ± 0.002 mm), and cross-sectional area (0.0011 ± 0.00007 vs. 0.00038 ± 0.00004 mm2). The UC II intervention elevated bone mineralization and formation and decreased bone resorption, inflammatory cytokines, and the oxidative stress. In addition, lower protein expression of IL-1β, RANKL, and TRAP in the UC II intervention group was observed. These findings suggested that UC II improved bones impaired by T2DM during ageing, and the likely mechanism was partly due to inhibition of inflammation and oxidative stress.

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Subchondral bone changes and cartilage damage

Equine Veterinary Journal ◽

10.1111/j.2042-3306.1999.tb03799.x ◽

1999 ◽

Vol 31 (2) ◽

pp. 94-95 ◽

Cited By ~ 34

Author(s):

E. L. RADIN

Keyword(s):

Subchondral Bone ◽

Cartilage Damage ◽

Bone Changes ◽

And Cartilage

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AB0094 Possitive effetcs of chiropractic manipulation on subchondral bone mineral density, cartilage damage and synovial inflammation in osteoarthritic rabbits

10.1136/annrheumdis-2018-eular.4713 ◽

2018 ◽

Author(s):

F.M. Conesa ◽

R. Fujikawa ◽

A. Mediero ◽

P. Gratal ◽

F. Mulero ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Subchondral Bone ◽

Cartilage Damage ◽

Synovial Inflammation ◽

Mineral Density ◽

Chiropractic Manipulation

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Raloxifene inhibits the overexpression of TGF-β1 in cartilage and regulates the metabolism of subchondral bone in rats with osteoporotic osteoarthritis

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2020.5142 ◽

2020 ◽

Author(s):

Shao-Hua Ping ◽

Fa-Ming Tian ◽

Hao Liu ◽

Qi Sun ◽

Li-Tao Shao ◽

...

Keyword(s):

Subchondral Bone ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Volume Fraction ◽

Clinical Indication ◽

Tartrate Resistant Acid Phosphatase ◽

Mineral Density ◽

Bone Volume Fraction ◽

Ovx Rats ◽

Tgf Β1

Overexpression of transforming growth factor-beta 1 (TGF-β1) and subchondral bone remodelling play key roles in osteoarthritis (OA). Raloxifene (RAL) reduces the serum level of TGF-β1 in postmenopausal women. However, the effect of RAL on TGF-β1 expression in articular cartilage is still unclear. Therefore, we aimed to investigate the protective effect of RAL on osteoporotic osteoarthritis via affecting TGF-β1 expression in cartilage and the metabolism of subchondral bone. Osteoporotic osteoarthritis was induced by a combination of anterior cruciate transection (ACLT) and ovariectomy (OVX). Rats were divided into five groups (n = 12): The sham group, the ACLT group, the OVX group, the ACLT + OVX group, and the RAL group (ACLT + OVX + RAL, 6.25 mg/kg/day for 12 weeks). Assessment was performed by histomorphology, microcomputed tomography (micro-CT) scan, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining. We found that severe cartilage degeneration was shown in the ACLT + OVX group. The histomorphological scores, the levels of TGF-β1, and its related catabolic enzymes and osteoclasts numbers in the ACLT + OVX group were higher than those in other groups (p < 0.05). Furthermore, structure model index (SMI) and trabecular spacing (Tb.Sp) were decreased (p < 0.05), while bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N) were increased by RAL compared with the ACLT + OVX group (p < 0.05). Our findings demonstrated that RAL in clinical doses retards the development of osteoporotic osteoarthritis by inhibiting the overexpression of TGF-β1 in cartilage and regulating the metabolism of subchondral bone. These results provide support for RAL in the expansion of clinical indication for prevention and treatment in postmenopausal osteoarthritis.

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Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-208268 ◽

2015 ◽

Vol 75 (11) ◽

pp. 1989-1997 ◽

Cited By ~ 31

Author(s):

Carmen Huesa ◽

Ana C Ortiz ◽

Lynette Dunning ◽

Laura McGavin ◽

Louise Bennett ◽

...

Keyword(s):

Subchondral Bone ◽

Pain Perception ◽

Weight Bearing ◽

Cartilage Damage ◽

Critical Role ◽

Cartilage Degradation ◽

Osteophyte Formation ◽

Bone Changes ◽

Experimental Osteoarthritis ◽

And Cartilage

ObjectiveProteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.MethodsOA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain.ResultsOsteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone.ConclusionsThis study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes.

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Structural Consequences of a Partial Anterior Cruciate Ligament Injury on Remaining Joint Integrity: Evidence for Ligament and Bone Changes Over Time in an Ovine Model

The American Journal of Sports Medicine ◽

10.1177/0363546520985279 ◽

2021 ◽

Vol 49 (3) ◽

pp. 637-648

Author(s):

Kristen I. Barton ◽

Bryan J. Heard ◽

Andres Kroker ◽

Johnathan L. Sevick ◽

Duncan A. Raymond ◽

...

Keyword(s):

Subchondral Bone ◽

Knee Injury ◽

Bone Microarchitecture ◽

Cruciate Ligament ◽

Mineral Density ◽

Trabecular Bone Mineral Density ◽

Bone Changes ◽

Articular Ligaments ◽

Anterior Cruciate ◽

Acl Transection

Background: Severe injury to the knee joint often results in accelerated posttraumatic osteoarthritis (PTOA). In an ovine knee injury model, altered kinematics and degradation of the cartilage have been observed at 20 and 40 weeks after partial anterior cruciate ligament (ACL) transection (p-ACL Tx) surgery. However, changes to the integrity of the remaining intact intra-articular ligaments (posterolateral [PL] band and posterior cruciate ligament [PCL]) as well as the subchondral bone after anteromedial (AM) band Tx remain to be characterized. Purpose: (1) To investigate histological alterations to the remaining intact intra-articular ligaments, the synovium, and the infrapatellar fat pad (IPFP) and (2) to quantify subchondral bone changes at the contact surfaces of the proximal tibia at 20 and 40 weeks after AM band Tx. Study Design: Descriptive laboratory study. Methods: Mature female Suffolk cross sheep were allocated into 3 groups: nonoperative controls (n = 6), 20 weeks after partial ACL transection (p-ACL Tx; n = 5), and 40 weeks after p-ACL Tx (n = 6). Ligament, synovium, and IPFP sections were stained and graded. Tibial subchondral bone microarchitecture was assessed using high-resolution peripheral quantitative computed tomography. Results: p-ACL Tx of the AM band led to significant change in histological scores of the PL band and the PCL at 20 weeks after p-ACL Tx ( P = .031 and P = .033, respectively) and 40 weeks after p-ACL Tx ( P = .011 and P = .029) as compared with nonoperative controls. Alterations in inflammatory cells and collagen fiber orientation contributed to the greatest extent of the combined histological score in the PL band and PCL. p-ACL Tx did not lead to chronic activation of the synovium or IPFP. Trabecular bone mineral density was strongly inversely correlated with combined gross morphological damage in the top and middle layers of the subchondral bone in the lateral tibial plateau for animals at 40 weeks after p-ACL Tx. Conclusion: p-ACL Tx influences the integrity (biology and structure) of remaining intact intra-articular ligaments and bone microarchitecture in a partial knee injury ovine model. Clinical Relevance: p-ACL Tx leads to alterations in structural integrity of the remaining intact ligaments and degenerative changes in the trabecular bone mineral density, which may be detrimental to the injured athlete’s knee joint in the long term.

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The anti-arthritis effect of sulforaphane, an activator of Nrf2, is associated with inhibition of both B cell differentiation and the production of inflammatory cytokines

PLoS ONE ◽

10.1371/journal.pone.0245986 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0245986

Author(s):

Su-Jin Moon ◽

Jooyeon Jhun ◽

Jaeyoon Ryu ◽

Ji ye Kwon ◽

Se-Young Kim ◽

...

Keyword(s):

B Cells ◽

Germinal Center ◽

Cartilage Damage ◽

Enzyme Linked Immunosorbent Assay ◽

Tartrate Resistant Acid Phosphatase ◽

Dependent Manner ◽

Autoantibody Production ◽

Murine Splenocytes ◽

Tnf Α ◽

Germinal Center B Cells

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor that plays a pivotal role in cellular defense against oxidative injury. Nrf2 signaling is involved in attenuating autoimmune disorders such as rheumatoid arthritis (RA). B cells play several roles in the pathogenesis of RA, such as in autoantibody production, antigen presentation, and T-cell activation. We investigated the anti-arthritic mechanisms of sulforaphane, an activator of Nrf2, in terms of its effect on B cells. To investigate the effect of sulforaphane on collagen-induced arthritis (CIA), sulforaphane was administered intraperitoneally after CIA induction. Hematoxylin and eosin-stained sections were scored for inflammation, pannus invasion, and bone and cartilage damage. We assessed the expression levels of inflammation-related factors by real-time PCR and the levels of various IgG subclasses by enzyme-linked immunosorbent assay. Sulforaphane treatment reduced the arthritis score and the severity of histologic inflammation in CIA mice. The joints from sulforaphane-treated CIA mice showed decreased expression of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, receptor activator of NF-κB ligand, and tartrate-resistant acid phosphatase. Sulforaphane-treated mice showed lower circulating levels of type-II-collagen-specific IgG, IgG1, and IgG2a. In vitro, sulforaphane treatment significantly reduced the differentiation of lipopolysaccharide-stimulated murine splenocytes into plasma B cells and germinal-center B cells. Finally, sulforaphane significantly inhibited the production of IL-6, TNF-α, and IL-17 by human peripheral blood mononuclear cells stimulated with an anti-CD3 monoclonal antibody in a dose-dependent manner. Inhibition of differentiation into plasma B and Germinal Center B cells may be the mechanism underlying the anti-arthritic effect of sulforaphane.

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