The reaction patterns of chondrocytes in osteoarthritis can be summarized in five categories: (1) proliferation and cell death (apoptosis); changes in (2) synthetic activity and (3) degradation; (4) phenotypic modulation of the articular chondrocytes; and (5) formation of osteophytes. In osteoarthritis, the primary responses are reinitiation of synthesis of cartilage macromolecules, the initiation of synthesis of types IIA and III procollagens as markers of a more primitive phenotype, and synthesis of active proteolytic enzymes. Reversion to a fibroblast-like phenotype, known as 'dedifferentiation', does not appear to be an important component. Proliferation plays a role in forming characteristic chondrocyte clusters near the surface, while apoptosis probably occurs primarily in the calcified cartilage.

Matrix metalloproteinase (MMP)-1, MMP-8 and MMP-13 are interstitial collagenases that degrade type II collagen in cartilage; this is a committed step in the progression of rheumatoid arthritis and osteoarthritis. Of these enzymes, the expression of MMP-1 and MMP-13 is substantially increased in response to IL-1 and tumor necrosis factor-α, and elevated levels of these collagenases are observed in arthritic tissues. Therefore, cytokine-mediated MMP-1 and MMP-13 gene regulation is an important issue in arthritis research. In this review, we discuss current models of MMP-1 and MMP-13 transcriptional regulation, with a focus on signaling intermediates and transcription factors that may be future targets for the development of new arthritis drugs.

Rheumatoid arthritis represents an excellent model in which to gain insights into the local and systemic effects of joint inflammation on skeletal tissues. Three forms of bone disease have been described in rheumatoid arthritis. These include: focal bone loss affecting the immediate subchondral bone and bone at the joint margins; periarticular osteopenia adjacent to inflamed joints; and generalized osteoporosis involving the axial and appendicular skeleton. Although these three forms of bone loss have several features in common, careful histomorphometric and histopathological analysis of bone tissues from different skeletal sites, as well as the use of urinary and serum biochemical markers of bone remodeling, provide compelling evidence that different mechanisms are involved in their pathogenesis. An understanding of these distinct pathological forms of bone loss has relevance not only with respect to gaining insights into the different pathological mechanisms, but also for developing specific and effective strategies for preventing the different forms of bone loss in rheumatoid arthritis.

BALB/c mice immunized with human cartilage proteoglycan (PG) develop arthritis accompanied by the production of autoantibodies to mouse cartilage PG. To determine whether the autoantibody isotype contributes to the onset and severity of arthritis, PG-specific serum IgG1 (Th2, IL-4-cytokine-supporting) and IgG2a (Th1, IFN-γ-controlling) concentrations were monitored during immunization with PG in IL-4-deficient and IFN-γ-deficient mice. Paradoxically, despite elevated IFN-γ, the PG-specific IgG1 isotype was significantly higher than the PG-specific IgG2a response, and the PG-specific IgG1 isotype was independent of IL-4. In contrast, the serum concentration of PG-specific IgG2a isotype was six times higher in IL-4-deficient mice than in wild-type controls. Moreover, the high concentration of PG-specific IgG2a isotype in IL-4-deficient mice corresponded to an increased severity of arthritis. The concentration of PG-specific IgG2a isotype was lower in IFN-γ-deficient mice than in wild-type mice, and the incidence and severity of arthritis also were significantly lower. Concentrations of PG-specific IgG2a isotype autoantibody correlated with the onset and severity of arthritis, suggesting a pathological role of this isotype, probably locally in the joint.

Background Bone remodelling is dependent on the balance between bone resorbing osteoclasts and bone forming osteoblasts. We have shown previously that osteoclasts contain gap-junctional protein connexin-43 and that a commonly used gap-junctional inhibitor, heptanol, can inhibit osteoclastic bone resorption. Since heptanol may also have some unspecific effect unrelated to gap-junctional inhibition we wanted to test the importance of gap-junctional communication to osteoclasts using a more specific inhibitor. Methods A synthetic connexin-mimetic peptide, Gap 27, was used to evaluate the contribution of gap-junctional communication to osteoclastic bone resorption. We utilised the well-characterised pit-formation assay to study the effects of the specific gap-junctional inhibitor to the survival and activity of osteoclasts. Results Gap 27 caused a remarked decrease in the number of both TRAP-positive mononuclear and multinucleated rat osteoclasts cultured on bovine bone slices. The decrease in the cell survival seemed to be restricted to TRAP-positive cells, whereas the other cells of the culture model seemed unaffected. The activity of the remaining osteoclasts was found to be diminished by measuring the percentage of osteoclasts with actin rings of all TRAP-positive cells. In addition, the resorbed area in the treated cultures was greatly diminished. Conclusions On the basis of these results we conclude that gap-junctional communication is essential for the action of bone resorbing osteoclasts and for proper remodelling for bone.

Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who lose up to 2% of their bone mass per month spent in Space. Despite important implications for Spaceflight travellers and bedridden patients on Earth the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development and has been proposed as a gravisensor. To investigate the role of PTHrP in microgravity-induced bone loss trabecular osteoblasts (TOs) from Pthrp+/+ and -/- mice were exposed to simulated microgravity for 6 days. Viability of TOs decreased in inverse proportion to PTHrP expression levels. Microarray analysis of Pthrp+/+ TOs after 6 days at 0g revealed expression changes in genes encoding prolactins,apoptosis and survival molecules bone metabolism and extra-cellular matrix composition proteins chemokines IGF family and Wnt-related signalling molecules. Importantly 88% of 0g-induced expression changes in Pthrp+/+ cells overlap those observed in Pthrp-/- cells in normal gravity. Pulsatile treatment with PTHrP1-36 peptide during microgravity exposure reversed a large proportion of 0g-induced changes in Pthrp+/+ TOs. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs. Total RNA samples extracted from Pthrp+/+and -/- trabecular osteoblasts (TOs) exposed for 6 days to simulated 0g in Synthecon rotating cell or left 6 days in culture at 1g. Cells had either been treated with a pulsatile treatment (2 h/day) of PTHrP1-36 peptide (10-8M) or received a change in growth medium. In total: 8 different conditions with 2 replicates each i.e. Pthrp+/+ TOs at 0g or 1g with or without PTHrP1-36 treatment and Pthrp-/- TOs at 0g or 1 g,with or without PTHrP1-36 treatment.

Bone resorption in the joints is the characteristic finding in patients with rheumatoid arthritis (RA). Osteoclast-like cells are present in the synovial tissues and invade the bone of patients with RA. The characteristics of these cells are not completely known. In the work reported here, we generated these cells from peripheral-blood monocytes from healthy individuals. The monocytes were co-cultured with nurse-like cells from synovial tissues of patients with RA (RA-NLCs). Within 5 weeks of culture, the monocytes were activated and differentiated into mononuclear cells positive for CD14 and tartrate-resistant acid phosphatase (TRAP). These mononuclear cells then differentiated into multinucleated giant bone-resorbing cells after stimulation with IL-3, IL-5, IL-7, and/or granulocyte-macrophage-colony-stimulating factor. TRAP-positive cells with similar characteristics were found in synovial fluid from patients with RA. These results indicate that multinucleated giant bone-resorbing cells are generated from monocytes in two steps: first, RA-NLCs induce monocytes to differentiate into TRAP-positive mononuclear cells, which are then induced by cytokines to differentiate into multinucleated giant bone-resorbing cells.

Articular and sterno-costal cartilages were isolated from skeletally-mature mice flown for 30 days on the BION-M1 mission. Samples were characterized histologically for proteoglycan loss and at the gene expression levels using Affymetrix gene arrays.

Cartilage serves multiple functions in the developing embryo and in postnatal life. Genetic mutations affecting cartilage development are relatively common and lead to skeletal malformations, dysfunction or increased susceptibility to disease or injury. Characterization of these mutations and investigation of the molecular pathways in which these genes function have contributed to an understanding of the mechanisms regulating skeletal patterning, chondrogenesis, endochondral ossification and joint formation. Extracellular growth and differentiation factors including bone morphogenetic proteins, fibroblast growth factors, parathyroid hormone-related peptide, extracellular matrix components, and members of the hedgehog and Wnt families provide important signals for the regulation of cell proliferation, differentiation and apoptosis. Transduction of these signals within the developing mesenchymal cells and chondrocytes results in changes in gene expression mediated by transcription factors including Smads, Msx2, Sox9, signal transducer and activator of transcription (STAT), and core-binding factor alpha 1. Further investigation of the interactions of these signaling pathways will contribute to an understanding of cartilage growth and development, and will allow for the development of strategies for the early detection, prevention and treatment of diseases and disorders affecting the skeleton.

Background Avascular necrosis of bone (osteonecrosis) can cause structural failure and subsequent deformation, leading to joint dysfunction and pain. Structural failure is the result of resorption of necrotic bone during revascularization, before new bone has formed or consolidated enough for loadbearing. Bone resorption can be reduced by bisphosphonates. If resorption of the necrotic bone could be reduced during the revascularization phase until sufficient new bone has formed, it would appear that structural failure could be avoided. Methods To test whether resorption of necrotic bone can be prevented, structural grafts were subjected to new bone ingrowth during systemic bisphosphonate treatment in a rat model. Results In rats treated with alendronate the necrotic bone was not resorbed, whereas it was almost entirely resorbed in the controls. Conclusion Systemic alendronate treatment prevents resorption of necrotic bone during revascularization. In patients with osteonecrosis, bisphosphonates may therefore prevent collapse of the necrotic bone.