Mechanical and biologic link between cartilage and subchondral bone in osteoarthritis

Zhang, Lizhi; Zheng, Hong-Ai; Jiang, Yao; Tu, Yihui; Pin, Jiang; Yang, Anli

doi:10.1002/acr.21640

Cited by 27 publications

(19 citation statements)

References 93 publications

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“…Soluble factors and mechanical signaling have been implicated in the parallel progression of OA cartilage loss and bone thickening (), both of which may explain the chondroprotection observed in PAR‐2 −/− mice. PAR‐2 −/− mice have fewer osteoblast precursors, and their bone marrow also generates fewer osteoclasts compared to WT mice (), whereas PAR‐1 −/− mice have normal numbers of osteoblast precursors () but increased numbers of osteoclasts () in injured bone.…”

Section: Discussionmentioning

confidence: 99%

Depletion of Protease‐Activated Receptor 2 but Not Protease‐Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms

Jackson

Moradi

Zaki

et al. 2014

Arthritis & Rheumatology

103

143

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Objective. To explore the involvement of proteaseactivated receptor 1 (PAR-1) and PAR-2 in the pathologic processes of osteoarthritis (OA) and to identify the cells/tissues primarily affected by ablation of PAR-1 or PAR-2 in mice.Methods. OA was induced in the joints of wildtype (WT), PAR-1 ؉/؉ , PAR-1 ؊/؊ , and PAR-2 ؊/؊ mice by destabilization of the medial meniscus (DMM), and scores of histologic features (cartilage aggrecan loss and erosion, subchondral bone sclerosis, osteophytes, and synovitis) were compared at 1, 4, and 8 weeks post-DMM. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/ activity were studied in cultures of mouse femoral head tissue with or without interleukin-1␣ (IL-1␣). At 1 week post-DMM, synovial expression of cytokines and metalloproteinase genes was measured by reverse transcription-polymerase chain reaction, and populations of inflammatory cells were quantified by flow cytometry.Results. Deletion of PAR-2, but not that of PAR-1, in mice significantly delayed the progression of cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR-1 or PAR-2 ablation on IL-1␣-induced cartilage degradation or chondrocyte metalloproteinase expression/activation. A low but significant level of synovitis persisted in mice subjected to DMM compared to that in control mice subjected to sham surgery, but no differences between the genotypes were seen 4 or 8 weeks post-DMM. One week after DMM, increased synovial expression of proinflammatory cytokines and metalloproteinase genes, along with increased levels of CD4؉ T cells, inflammatory monocytes, and activated macrophages, were seen in all genotypes. However, there was a significant reduction in the percentage of activated macrophages in PAR-2 ؊/؊ mice compared to PAR-1 ؊/؊ and WT mice.Conclusion. Deletion of PAR-2, but not that of PAR-1, results in a significant decrease in DMMinduced cartilage damage. The chondroprotection in PAR-2 ؊/؊ mice appears to occur indirectly through modulation of extracartilaginous events such as subchondral bone remodeling and synovial macrophage activation, rather than through alteration of chondrocyte catabolic responses.The synovial joint is an "organ" with communication and interdependence between the component tissues and cells necessary for maintenance of normal articular function (1). Osteoarthritis (OA) is the most common arthropathy, and although progressive loss of articular cartilage is pathognomonic, there are varying

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Section: Discussionmentioning

confidence: 99%

Depletion of Protease‐Activated Receptor 2 but Not Protease‐Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms

Jackson

Moradi

Zaki

et al. 2014

Arthritis & Rheumatology

103

143

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“…This suggests that the inflammatory conditions developed because of altered biomechanical stress in ACL-transected joints advances chondrocytes toward terminal differentiation. This process lays a foundation for osteophyte formation in OA joints as well as cartilage thinning by expansion of subchondral bone into cartilage (42,43). In IL-3-injected OA mice, a proper cartilage zonation reflecting the structural integrity of cartilage was maintained along with the maintenance of zone-specific phenotype of chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

Kour

Garimella

Shiroor

et al. 2016

The Journal of Immunology

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Osteoarthritis (OA) is a chronic disease of articular joints that leads to degeneration of both cartilage and subchondral bone. These degenerative changes are further aggravated by proinflammatory cytokines including IL-1β and TNF-α. Previously, we have reported that IL-3, a cytokine secreted by activated T cells, protects cartilage and bone damage in murine models of inflammatory and rheumatoid arthritis. However, how IL-3 protects cartilage degeneration is not yet known. In this study, we investigated the role of IL-3 on cartilage degeneration under both in vitro and in vivo conditions. We found that both mouse and human chondrocytes show strong expression of IL-3R at gene and protein levels. IL-3 increases the expression of mouse chondrocyte-specific genes, Sox9 and collagen type IIa, which were downregulated by IL-1β. Moreover, IL-3 downregulated IL-1β– and TNF-α–induced expression of matrix metalloproteinases in both mouse and human chondrocytes. Interestingly, IL-3 reduces the degeneration of articular cartilage and subchondral bone microarchitecture in a mouse model of human OA. Moreover, IL-3 showed the preventive and therapeutic effects on cartilage degeneration induced by IL-1β in micromass pellet cultures of human mesenchymal stem cells. Thus, to our knowledge, we provide the first evidence that IL-3 has therapeutic potential in amelioration of degeneration of articular cartilage and subchondral bone microarchitecture associated with OA.

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“…Increased subchondral uptake of radiolabelled bisphosphonates38 and MRI-defined bone marrow lesions6 are each associated with OA pain, and subchondral osteoclast numbers are increased in OA both in man10 and rats 20 39. Subchondral bone pathology may contribute to cartilage damage in OA (see references in Zhang et al 40). Furthermore, osteophytes are innervated by sensory nerves originating in the subchondral bone, and may be a source of OA pain 41.…”

Section: Discussionmentioning

confidence: 99%

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

Sagar

Ashraf

et al. 2013

Ann Rheum Dis

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BackgroundIncreased subchondral bone turnover may contribute to pain in osteoarthritis (OA).ObjectivesTo investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain.MethodsMale Sprague Dawley rats (140–260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1–15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group.ResultsPre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage.ConclusionsOur data suggest that early targeting of osteoclasts may reduce pain associated with OA.

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Mechanical and biologic link between cartilage and subchondral bone in osteoarthritis

Cited by 27 publications

References 93 publications

Depletion of Protease‐Activated Receptor 2 but Not Protease‐Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms

Depletion of Protease‐Activated Receptor 2 but Not Protease‐Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms

IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

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