Reduction of knee joint load suppresses cartilage degeneration, osteophyte formation, and synovitis in early-stage osteoarthritis using a post-traumatic rat model.

The purpose of this study was to clarify the histological effect of reducing the loading to knee on cartilage degeneration, osteophyte formation, and synovitis in early-stage osteoarthritis (OA) using a post-traumatic rat model. Ten male rats were randomly allocated into two experimental groups: OA induction by surgical destabilization of medial meniscus (DMM, OA group) and hindlimb suspension after OA induction by DMM (OAHS group). The articular cartilage, osteophyte formation, and synovial membrane in the medial tibiofemoral joint were analyzed histologically and histomorphometrically at 2 and 4 weeks after surgery. The histological scores and changes in articular cartilage and osteophyte formation were significantly milder and slower in the OAHS group than in the OA group. At 2 and 4 weeks, there were no significant differences in cartilage thickness and matrix staining intensity between both the groups, but chondrocytes density was significantly lower in the OA group. Synovitis was milder in OAHS group than in OA group at 2 weeks. Reducing knee joint loading inhibited histological OA changes in articular cartilage, osteophyte formation, and synovial inflammation. This result supports the latest clinical guidelines for OA treatment. Further studies using biochemical and mechanical analyses are necessary to elucidate the mechanism underlying delayed OA progression caused by joint-load reduction.

Which Osteotomy for Osteonecrosis of the Femoral Head and Which Patient for the Osteotomy?

Transtrochanteric curved varus osteotomy (TCVO) and transtrochanteric rotational osteotomy (TRO) are joint-preserving procedures for osteonecrosis of the femoral head. The purpose of this review is to provide up-to-date guidelines for the osteotomies. One retrospective comparison revealed that TCVO has shorter operation time, less bleeding, lower incidence of osteophyte formation, and lower rate of secondary collapse. To obtain successful results of the osteotomy, the patient should be younger than 40 years and should have a body mass index of less than 24 kg/m2. The osteotomy should be performed in early stages of femoral head osteonecrosis before marked collapse of the femoral head. The patient should have a medium-size lesion and an enough viable bone to restore the intact articular surface and subchondral bone in the weight-bearing area.

Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis.

OBJECTIVE: To investigate the impact of systemic inhibition of interleukin 6 (IL-6) or signal transducer and activator of transcription (Stat3) in an experimental model of osteoarthritis (OA). METHODS: Expression of major catabolic and anabolic factors of cartilage was determined in IL-6-treated mouse chondrocytes and cartilage explants. The anti-IL-6-receptor neutralising antibody MR16-1 was used in the destabilisation of the medial meniscus (DMM) mouse model of OA. Stat3 blockade was investigated by the small molecule Stattic ex vivo and in the DMM model. RESULTS: In chondrocytes and cartilage explants, IL-6 treatment reduced proteoglycan content with increased production of matrix metalloproteinase (MMP-3 and MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4 and ADAMTS-5). IL-6 induced Stat3 and extracellular signal-regulated kinase (ERK) 1/2 signalling but not p38, c-Jun N-terminal kinase or Akt. In the DMM model, Stat3 was activated in cartilage, but neither in the synovium nor in the subchondral bone. Systemic blockade of IL-6 by MR16-1 alleviated DMM-induced OA cartilage lesions, impaired the osteophyte formation and the extent of synovitis. In the same model, Stattic had similar beneficial effects on cartilage and osteophyte formation. Stattic, but not an ERK1/2 inhibitor, significantly counteracted the catabolic effects of IL-6 on cartilage explants and suppressed the IL-6-induced chondrocytes apoptosis. CONCLUSION: IL-6 induces chondrocyte catabolism mainly via Stat3 signalling, a pathway activated in cartilage from joint subjected to DMM. Systemic blockade of IL-6 or STAT-3 can alleviate DMM-induced OA in mice.

Bevacizumab, an anti-vascular endothelial growth factor antibody, inhibits osteoarthritis.

INTRODUCTION: Angiogenesis is an important factor in the development of osteoarthritis (OA). We investigated the efficacy of bevacizumab, an antibody against vascular endothelial growth factor and an inhibitor of angiogenesis, in the treatment of OA using a rabbit model of anterior cruciate ligament transection. METHODS: First, we evaluated the response of gene expression and histology of the normal joint to bevacizumab treatment. Next, in a rabbit model of OA induced by anterior cruciate ligament transection, we used macroscopic and histological evaluations and real-time polymerase chain reaction (PCR) to examine the responses to intravenous (systemic) administration of bevacizumab (OAB IV group). We also investigated the efficacy of intra-articular (local) administration of bevacizumab in OA-induced rabbits (OAB IA group). RESULTS: Histologically, bevacizumab had no negative effect in normal joints. Bevacizumab did not increase the expression of genes for catabolic factors in the synovium, subchondral bone, or articular cartilage, but it increased the expression of collagen type 2 in the articular cartilage. Macroscopically and histologically, the OAB IV group exhibited a reduction in articular cartilage degeneration and less osteophyte formation and synovitis compared with the control group (no bevacizumab; OA group). Real-time PCR showed significantly lower expression of catabolic factors in the synovium in the OAB IV group compared with the OA group. In articular cartilage, expression levels of aggrecan, collagen type 2, and chondromodulin-1 were higher in the OAB IV group than in the OA group. Histological evaluation and assessment of pain behaviour showed a superior effect in the OAB IA group compared with the OAB IV group 12 weeks after administration of bevacizumab, even though the total dosage given to the OAB IA group was half that received by the OAB IV group. CONCLUSIONS: Considering the dosage and potential adverse effects of bevacizumab, the local administration of bevacizumab is a more advantageous approach than systemic administration. Our results suggest that intra-articular bevacizumab may offer a new therapeutic approach for patients with post-traumatic OA.

Bone anabolic changes progress in psoriatic arthritis patients despite treatment with methotrexate or tumour necrosis factor inhibitors.

OBJECTIVES: To investigate whether methotrexate or tumour necrosis factor inhibitors (TNFi) affect osteophyte formation in patients with psoriatic arthritis (PsA). METHODS: 41 patients with PsA were examined for the presence of osteophytes and erosions at the metacarpophalangeal joints by high-resolution micro-CT imaging. The size of each individual lesion was quantified at baseline and 1-year follow-up in PsA patients treated with TNFi (N=28) or methotrexate (N=13). Groups were comparable for age, sex, disease duration and activity and baseline burden of osteophytes. RESULTS: In total, 415 osteophytes (TNFi N=284, methotrexate N=131) were detected. Osteophyte size increased significantly from baseline to follow-up in the TNFi group (mean±SEM change +0.23±0.02 mm; p<0.0001) and the methotrexate group (+0.27±0.03 mm, p<0.0001). In both treatment groups, the majority of osteophytes showed progression (TNFi 54.3%, methotrexate 61.1%), whereas regression of lesions was rare (less than 10%). In contrast to osteophytes, clinical disease activity decreased in both groups of PsA patients and erosions showed an arrest of progression in both groups. CONCLUSIONS: Osteophytes progress in PsA patients treated with either methotrexate or TNFi. These data provide the first evidence that pathological bone formation in the appendicular skeleton of patients with PsA is not affected by current antirheumatic treatment strategies.

Potential mechanism of alendronate inhibition of osteophyte formation in the rat model of post-traumatic osteoarthritis: evaluation of elemental strontium as a molecular tracer of bone formation.

OBJECTIVE: To employ elemental Strontium as a tracer of bone turnover, in the presence (or absence) of the bisphosphonate drug Alendronate, in order to spatially map osteophytogenesis and other bone turnover in rats developing post-traumatic secondary osteoarthritis (PTOA). METHODS: PTOA was induced in rats by medial meniscectomy surgery. We utilized in-vivo microfocal computed tomography (CT) to follow bony adaptations in groups for 8 weeks after surgery, either with or without alendronate treatment. Electron probe microanalysis (EPMA) was used to detect Strontium incorporation in mineralizing tissues. Histologic studies were conducted on the same samples using Safranin-O/fast green and Tetrachrome staining of decalcified sections to examine articular cartilage health and osteophyte formation at the sites of elemental Strontium deposition. RESULTS: EPMA revealed uniform incorporation of Strontium over actively remodeling trabecular surfaces in normal control rats. That pattern was significantly altered after meniscectomy surgery resulting in greater Strontium signal at the developing osteophyte margins. Alendronate treatment inhibited osteophyte development by 40% and 51% quantified by micro-CT volumetric measurements at 4 and 8 weeks after surgery, respectively. Osteophytes in the alendronate group were more cartilaginous in composition [i.e., lower bone mineral density (BMD)] compared to the untreated group. Histological analysis confirmed the osteophyte inhibitory effect of alendronate, and also verified reduced degeneration of the articular cartilage compared to untreated rats. CONCLUSION: Our study confirmed that alendronate administration will reduce osteophyte formation in a rat model of post-traumatic osteoarthritis, partially through the inhibition of secondary remodeling of osteophytes. Our study is the first to employ elemental Strontium as a tracer of bone turnover in the pathogenesis of osteoarthritis and to assess the efficacy of bisphosphonate antiresorptive drug interventions on osteophytogenesis.