Osteophyte Formation In Osteoarthritis Research Articles

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

E72 Distribution of cells and extracellular matrix in the marginal synovium during the postnatal period

Abstract Introduction The marginal transitional zone of the joint is of fundamental importance in joint pathology. The normal marginal synovium takes part in articular cartilage repair (Adachi et al. 2012). The inflamed marginal synovium, in turn, promotes irreversible damage to the adjacent cartilage and bone (Hitchon & El-Gabalawy, 2011). Early erosive damage in rheumatoid arthritis and osteophyte formation in osteoarthritis occurs primarily here (Allard et al. 1990). Objectives The morphology of the marginal synovium from birth till the 90th day was studied using the hip joints of Wistar rats. Methods The collection of joints was carried out on the first, seventh, 14th, 30th, 45th, 60th and 90th day (six rats in each group, 42 in total). Joints were fixed, decalcified and dehydrated. Histologic paraffine sections were stained with Mallory's trichrome and Hart's elastin staining, analyzed at the acetabular labrum by light microscopy (χ100), morphometrical and statistical (P < 0.05) methods with extrapolation to humans (Sengupta, 2013). The obtained data were presented as percentages. Results In the marginal synovium, cells and components of the extracellular matrix, which are typical for fibrous connective tissue, could be seen. The synovial lining cells are embedded in the modified basement membrane which includes collagen and elastic fibers. They form a three-dimensional reticulum in it and adjacent synovial subintima. Vessels of the microcirculatory bed are also widely represented in the marginal synovium. The overall quantity of collagen fibers increased gradually, exceeding on the 90th day (approximately corresponds to 18–19 human years) that of newborns by one and a half times (48.92 ± 3.39 vs 72.17 ± 7.77; P = 0.023). The number of arranged collagen fibers increased gradually, exceeding on the 90th day that of newborns almost twofold (37.25 ± 3.21 vs 60.08 ± 5.99; P = 0.008). The area of distribution of disarranged collagen fibers in newborns was almost four and a half times less than the overall quantity of collagen fibers (11.67 ± 1.03 vs 48.92 ± 3.39; P < 0.001) and did not change substantially throughout the experiment. The number of elastic fibers increased till the 30th day (0.63 ± 0.11 vs 18.3 ± 1.25; P < 0.001) and did not undergo significant changes later. In newborns, the area of distribution of ground substance was not considerably higher than the ratio of disarranged collagen fibers (10.42 ± 1.8 vs 11.67 ± 1.03; P = 0.562) and did not undergo substantial changes later. The distribution density of vessels increased till the 30th-45th day (4.5 ± 0.67 vs 7.5 ± 0.82 and 7.7 ± 0.54; P < 0.001; approximately corresponds to the 9th and 14th human years respectively), followed by a gradual decrease from the 60th day (7.05 ± 0.72; roughly corresponds to the 16th human years). The maximum number of cells was in newborns. Subsequently, it gradually decreased and was almost three times less on the 90th day than that of newborns (38.01 ± 3.06 vs 12.58 ± 1.53; P < 0.001). Conclusion The morphogenesis of the marginal synovium during the postnatal period is accompanied by a gradual decrease in the number of cells, an increase in the area occupied by elastic and arranged collagen fibers with a relatively constant distribution density of disarranged collagen fibers and ground substance together with an undulatory pattern in the distribution of vessels. These peculiarities emphasize the morphological uniqueness of the marginal transitional zone, which forms the innate nonspecific barrier between the joint capsule and the articular cartilage, and thereby provides the necessary anatomical and physiological integrity of the joint as a whole organ. Knowledge about the patterns of morphogenesis of the marginal synovium will help in the future to analyze the modeled pathological or boundary states in it. Ethics The study was approved by the ethics committee of the Zaporizhzhia State Medical University.

Enhanced SOCS3 in osteoarthiritis may limit both proliferation and inflammation

Osteoarthritis (OA) is a degenerative joint disease that is characterized by localized inflammatory and secondary proliferative changes. Suppressor of cytokine signaling 3 (SOCS3) is elevated during OA development. We investigated the effects of this protein on human chondrocyte survival in OA and the inflammatory response together with the mechanisms of these effects. Small interfering RNA (siRNA) was used to knock down the expression of SOCS3 in interleukin(IL)-1β-induced primary human osteoarthritic chondrocytes. We found that siRNA-mediated SOCS3 knock-down in human osteoarthritic chondrocytes increased production of IL-1β-induced prostaglandin E2, cell growth, transcript level and nuclear translocation of cyclin D1. Silencing of SOCS3 resulted in altered expression of nuclear factor-kappa-B (NF-κB) and cyclooxygenase (COX2). Our findings indicate that enhanced SOCS3 could have contradictory influences on OA development. SOCS3 might protect damaged joints by its anti-inflammatory effect and by inhibition of over-augmented cartilage tissue repair, which could exhibit inhibitory properties for joint inflammation, abnormal chondrocyte clustering and osteophyte formation in OA. On the other hand, SOCS3 might reduce chondrocyte growth response, which would delay repair of subchondral cancellous bone damage in OA owing to its anti-proliferation effect. The anti-inflammation and growth inhibition effects exhibited by enhanced SOCS3 in OA appear to be related to its capacity to down-regulate expression levels of NF-κB and COX2.

Alarmin S100A9 Induces Proinflammatory and Catabolic Effects Predominantly in the M1 Macrophages of Human Osteoarthritic Synovium

The alarmins S100A8 and S100A9 have been shown to regulate synovial activation, cartilage damage, and osteophyte formation in osteoarthritis (OA). Here we investigated the effect of S100A9 on the production of proinflammatory cytokines and matrix metalloprotease (MMP) in OA synovium, granulocyte macrophage colony-stimulating factor (GM-CSF)-differentiated/macrophage colony-stimulating factor (M-CSF)-differentiated macrophages, and OA fibroblasts. We determined which cell types in the synovium produced S100A8 and S100A9. Further, the production of proinflammatory cytokines and MMP, and the activation of canonical Wnt signaling, was determined in human OA synovium, OA fibroblasts, and monocyte-derived macrophages following stimulation with S100A9. We observed that S100A8 and S100A9 were mainly produced by GM-CSF-differentiated macrophages present in the synovium, and to a lesser extent by M-CSF-differentiated macrophages, but not by fibroblasts. S100A9 stimulation of OA synovial tissue increased the production of the proinflammatory cytokines interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor-α. Additionally, various MMP were upregulated after S100A9 stimulation. Experiments to determine which cell type was responsible for these effects revealed that mainly stimulation of GM-CSF-differentiated macrophages and to a lesser extent M-CSF-differentiated macrophages with S100A9 increased the expression of these proinflammatory cytokines and MMP. In contrast, stimulation of fibroblasts with S100A9 did not affect their expression. Finally, stimulation of GM-CSF-differentiated, but not M-CSF-differentiated macrophages with S100A9 activated canonical Wnt signaling, whereas incubation of OA synovium with the S100A9 inhibitor paquinimod reduced the activation of canonical Wnt signaling. Predominantly mediated by M1-like macrophages, the alarmin S100A9 stimulates the production of proinflammatory and catabolic mediators and activates canonical Wnt signaling in OA synovium.

A5.18 BMP2 requires TGF-BETA to induce osteophytes during experimental osteoarthritis

Background and ObjectivesOsteophytes are a major hallmark of osteoarthritis (OA). Both TGF-beta and BMP2 can induce osteophytes in murine knee joints. We demonstrated that TGF-beta could induce chondrogenesis in mesenchymal...

OP0242 Serum Indian Hedgehog (IHH) Levels Are Increased in Patients with Ankylosing Spondylitis (AS). Anti-TNF a Treatment Decreases Serum IHH Levels in Patients with as and Affects the Expression of Functional Target Genes in a Cell Line Model

BackgroundThe molecular pathways involved in the process of new bone formation in ankylosing spondylitis (AS) are not entirely known. However, data suggests that this process is linked to the reactivation...

Hylan G-F 20 maintains cartilage integrity and decreases osteophyte formation in osteoarthritis through both anabolic and anti-catabolic mechanisms

To perform a molecular mechanism-based investigation of the chondroprotective potential of hylan G-F 20. The effects of hylan G-F 20 on IL-1β-induced glycosaminoglycan (GAG) depletion and matrix metalloproteinase (MMP) expression in bovine and human cartilage explants were evaluated. Three weekly intra-articular hylan G-F 20 or control injections were administered 4weeks post-operatively to rabbits with surgically induced osteoarthritis (OA). Cartilage histopathologic scores and osteophyte size were evaluated at 1, 4, and 8weeks post-injections. Histomorphometry and immunostaining were used to quantify cartilage area and type II collagen (Col II) intensity, and real-time polymerase chain reaction (PCR) was used to examine the mRNA levels of Col2A1, MMP-13, -16 and IL-1β at 1week. Hylan G-F 20 retained GAG in IL-1β-exposed bovine and human cartilage explants and abrogated IL-1β-mediated increases in MMP-1, -3, and -13 in human explant culture. Hylan G-F 20‒treated OA joints had significantly better cartilage integrity at 1 and 4weeks post-treatment and significantly smaller osteophytes at 4weeks compared with control. Col2A1 mRNA increased with hylan G-F 20 treatment, which correlated with a trend toward increased Col II immunostaining. MMP-13 and -16 mRNAs increased in OA cartilage, but were not significantly altered by hylan G-F 20. IL-1β mRNA was undetectable in cartilage and unaltered in the synovium. Hylan G-F 20 improved cartilage integrity and decreased osteophyte formation in the rabbit model of OA. Our results suggest that hylan G-F 20 may stimulate cartilage repair by increasing Col II, and inhibit IL-1β-mediated matrix degradation by decreasing MMPs.

Matrix Gla Protein Polymorphism, But Not Concentrations, Is Associated with Radiographic Hand Osteoarthritis

Factors associated with mineralization and osteophyte formation in osteoarthritis (OA) are incompletely understood. Genetic polymorphisms of matrix Gla protein (MGP), a mineralization inhibitor, have been associated clinically with conditions of abnormal calcification. We therefore evaluated the relationship of MGP concentrations and polymorphisms at the MGP locus to hand OA. Ours was an ancillary study to a 3-year randomized trial assessing the effect of vitamin K supplementation on vascular calcification and bone loss among community-dwelling elders. We studied participants who had serum MGP concentration measured and DNA genotyped for 3 MGP genetic polymorphisms (rs1800802, rs1800801, and rs4236), and who had hand radiographs. We evaluated the cross-sectional associations of serum MGP and the 3 MGP genetic polymorphisms, respectively, with radiographic hand OA using logistic regression with generalized estimating equations, adjusting for potential confounders. Radiographic hand OA in ≥ 1 joint was present in 71% of the 376 participants (mean age 74 years, mean body mass index 28 kg/m(2), 59% women). No significant association between serum MGP concentrations and radiographic hand OA was found [adjusted OR 1.0 (ref), 1.40, 1.21, and 1.21 for quartiles 1-4, respectively]. Homozygosity of the rs1800802 minor allele was associated with 0.56 times lower prevalence of hand OA compared with having ≥ 1 major allele at this locus (95% CI 0.32-0.99, p = 0.046). There may be an association between hand OA and genetic polymorphism at the MGP locus that is not reflected by total MGP serum concentrations. Further studies are warranted to replicate and elucidate potential mechanisms underlying these observed associations.

Bone Mineral Density Is Not Related to Osteophyte Formation in Osteoarthritis of the Hip

Reports have suggested that bone mineral density (BMD) is higher in patients with osteoarthritis (OA) of the hip than in healthy controls. Various types of OA of the hip caused by osteophyte formation were observed on radiographs during progression to the advanced degenerative stage, and the preoperative type of OA was reported to influence the results of surgical treatment. However, the mechanism underlying the development of different types of OA is still unknown. We measured BMD of patients with hip OA and determined whether higher BMD was observed in patients with osteophyte formation than in those without osteophytes. We measured BMD of the lumbar spine, radius, and calcaneus using dual-energy x-ray absorptiometry in 88 women who were scheduled to undergo total hip arthroplasty for endstage OA. Hips were evaluated for osteophyte formation using Bombelli's classification; 31 were graded as atrophic type, 30 as normotrophic, and 27 as hypertrophic. BMD at different skeletal sites were compared among the 3 types of OA. No significant difference in BMD of the lumbar spine, ultradistal radius, mid-radius, or calcaneus was observed among the atrophic, normotrophic, and hypertrophic types of OA. Our data suggest that osteophyte formation is not related to general BMD. Factors other than general bone status, for example the morphology of the hip joint, need to be analyzed to determine the pathomechanism of osteophyte formation in the osteoarthritic hip.

Akt1 in murine chondrocytes controls cartilage calcification during endochondral ossification under physiologic and pathologic conditions

To examine the role of the phosphoinositide-dependent serine/threonine protein kinase Akt1 in chondrocytes during endochondral ossification. Skeletal phenotypes of homozygous Akt1-deficient (Akt1(-/-)) mice and their wild-type littermates were compared in radiologic and histologic analyses. An experimental osteoarthritis (OA) model was created by surgically inducing instability in the knee joints of mice. For functional analyses, we used primary costal and articular chondrocytes from neonatal mice and mouse chondrogenic ATDC5 cells with retroviral overexpression of constitutively active Akt1 or small interfering RNA (siRNA) for Akt1. Among the Akt isoforms (Akt1, Akt2, and Akt3), Akt1 was the most highly expressed in chondrocytes, and the total level of Akt protein was decreased in Akt1(-/-) chondrocytes, indicating a dominant role of Akt1. Akt1(-/-) mice exhibited dwarfism with normal proliferative and hypertrophic zones but suppressed cartilage calcification in the growth plate compared with their wild-type littermates. In mice with surgically induced OA, calcified osteophyte formation, but not cartilage degradation, was prevented in the Akt1(-/-) joints. Calcification was significantly suppressed in cultures of Akt1(-/-) chondrocytes or ATDC5 cells overexpressing siRNA for Akt1 and was enhanced in ATDC5 cells overexpressing constitutively active Akt1. Neither proliferation nor hypertrophic differentiation was affected by the gain or loss of function of Akt1. The expression of ANK and nucleotide pyrophosphatase/phosphodiesterase 1, which accumulate pyrophosphate, a crucial calcification inhibitor, was enhanced by Akt1 deficiency or siRNA for Akt1 and was suppressed by constitutively active Akt1. Our findings indicate that Akt1 in chondrocytes controls cartilage calcification by inhibiting pyrophosphate during endochondral ossification in skeletal growth and during osteophyte formation in OA.

変形性股関節症における roof osteophyte 形成に関する要因

変形性股関節症における roof osteophyte 形成に関する要因

Progressive patterns of degenerative arthritis in scaphoid nonunion demonstrated by three-dimensional computed tomography

Degenerative arthritis following scaphoid nonunion was studied in 28 patients (29 wrists) using X-ray computed tomography and three-dimensional computed tomography (3-DCT). Degenerative changes were observed in 18 wrists with plain radiography and 27 wrists with 3-DCT. 3-DCT imaging more readily revealed osteophyte formation in osteoarthritis than plain radiography. 3-DCT images showed degenerative changes in the distal fragment of the scaphoid earlier than plain radiography. We found three stages of osteophyte formation in the radioscaphoid joint using 3-DCT. In the first stage, a linear osteophyte formed along the most radial portion of the distal fragment of the scaphoid. In the second stage, the radial styloid became pointed. In the third stage, the osteophyte on the distal fragment enlarged and lay over the dorsum of the radioscaphoid joint and other intercarpal joints.

The sesamoid bones of the hands and feet: participators in arthritis.

The sesamoids generally appear as small ovoid bones adjacent to articulations or at sites where tendons are angled about osseous surfaces. At either location they participate in joint afflictions, the pattern of abnormality being remarkably constant and predictable. Sesamoids may demonstrate osseous erosion in rheumatoid arthritis, bony proliferation or "whiskering" in rheumatoid variants, joint space narrowing and bony ankylosis in septic arthritis, and eburnation and osteophyte formation in osteoarthritis and diffuse idiopathic skeletal hyperostosis. These changes become particularly important when they occur in the absence of significant adjacent articular disease. In these instances, recognition of sesamoid abnormalities allows accurate radiographic diagnosis.