DICKKOPF-1 IS A MASTER REGULATOR OF JOINT REMODELING PDF

Bagor WalshTania N. Gravallese Arthritis and rheumatism References Publications referenced by this paper. You are an Editor for the journal in which the article is published. Figure 3 New bone formation next to inflamed joints is increased upon blockade of DKK We identified tumor necrosis factor-alpha TNF as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. Wound scratching was used to induce the migration of FLSs [ 26 ]. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass.

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How Does Joint Remodeling Work? Abstract Remodeling of joints is a key feature of inflammatory and degenerative joint disease. Bone erosion, cartilage degeneration and growth of bony spurs termed osteophytes are key features of structural joint pathology in the course of arthritis, which lead to impairment of joint function. Understanding their molecular mechanisms is essential to tailor targeted therapeutic approaches to protect joint architecture from inflammatory and mechanical stress.

This addendum summarizes the new insights in the molecular regulation of bone formation in the joint and its relation to bone resorption. It describes how inflammatory cytokines impair bone formation and block the repair response of joints towards inflammatory stimuli. It particularly points out the key role of Dickkopf-1 protein, a regulator of the Wingless signaling and inhibitor of bone formation.

This new link between inflammation and bone formation is also crucial for explaining the generation of osteophytes, bony spurs along joints, which are characterized by new bone and cartilage formation.

This mechanism is largely dependent on an activation of wingless protein signaling and can lead to complete joint fusion. This addendum summarized the current concepts of joint remodeling in the limelight of these new findings. Key words: joint remodeling, arthritis, bone formation, bone erosion, osteoblasts, osteoclasts, Dickkopf, wingless proteins Joints face profound remodeling in the course of arthritis. In humans, pathologic joint remodeling manifests as i destruction of joints due to bone erosion rheumatoid arthritis , ii fusion of joints due to formation of bony spurs such as osteophytes, spondylophytes and syndesmophytes ankylosing spondylitis or iii a mixture of both changes psoriatic arthritis.

The molecular mechanisms determining these different forms of joint remodeling are not fully clarified, Insights in these mechanisms however are a clue to a deeper understanding of the architectural changes of human joints. Similar to systemic bone turnover, which most is most prominent in the trabecular bone compartment of the spine and long bones, joints are hot spots of bone remodeling during inflammatory disease.

Cytokines expressed by inflammatory cells in the synovial membrane regulate local bone homeostasis and enable to remodel joints during disease—a process which can either lead to crippling and functional loss or to fusion and stabilization of the affected joint.

Rheumatoid arthritis is characterized by bone erosions, which are the result of an enhanced bone resorption. In rheumatoid arthritis osteoclasts, the primary bone resorbing cells, accumulate and degrade the periarticular bone as well as the mineralized cartilage.

Bone formation itself is regulated by growth factors and hormones, which stimulate differentiation and activity of osteoblasts. Typical regulators of bone formation constitute parathyroid hormone, prostaglandins, bone morphogenic proteins BMPs and wingless proteins Wnt. DKK-1 is highly expressed in inflammatory lesions of experimental arthritis and human rheumatoid arthritis.

Inhibition of DKK-1 in mice completely abolishes bone erosions in different models of experimental arthritis and leads to increased bone growth, which manifests as osteophyte formation in the joint.

The fact that TNF and presumably also other inflammatory mediators induce both proteins explains the profound negative effect of inflammation on bone. Inflammation uncouples the balance between bone resorption and formation, enhancing the former by inducing RANKL and by repressing the latter by DKK OPG is induced by Wnt proteins and shifts the balance from bone resorption to bone formation. In contrast to rheumatoid arthritis joints in ankylosing spondylitis and also in degenerative joint disease osteoarthritis show an attempt towards joint fusion rather than joint destruction.

These bony spurs are the result of endochondral bone formation starting from the periosteum close to the joints, where osteoblasts differentiate build up bone matrix.

We could demonstrate that Wnt proteins are crucially involved in this process since inhibition of DKK-1 lead to emergence of osteophytes and even complete fusion of joints.

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Dickkopf-1 is a master regulator of joint remodeling

How Does Joint Remodeling Work? Abstract Remodeling of joints is a key feature of inflammatory and degenerative joint disease. Bone erosion, cartilage degeneration and growth of bony spurs termed osteophytes are key features of structural joint pathology in the course of arthritis, which lead to impairment of joint function. Understanding their molecular mechanisms is essential to tailor targeted therapeutic approaches to protect joint architecture from inflammatory and mechanical stress. This addendum summarizes the new insights in the molecular regulation of bone formation in the joint and its relation to bone resorption. It describes how inflammatory cytokines impair bone formation and block the repair response of joints towards inflammatory stimuli. It particularly points out the key role of Dickkopf-1 protein, a regulator of the Wingless signaling and inhibitor of bone formation.

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Dickkopf-1 is a master regulator of joint remodeling.

Shakarisar Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. S1available at Rheumatology Online. Citations Publications citing this paper. Showing of extracted citations.

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DICKKOPF-1 IS A MASTER REGULATOR OF JOINT REMODELING PDF

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How Does Joint Remodeling Work?

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