TGF-β and osteoarthritis—the good and the bad

Bush, Jason; Beier, Frank

doi:10.1038/nm.3228

Cited by 60 publications

(55 citation statements)

References 15 publications

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“…(33–36) Excessive TGF-β signaling is recognized as a common mechanism in aberrant osteogenesis as demonstrated in Camurati–Engelmann disease (CED), osteogenesis imperfecta (OI), and OA. (19,22,32,37,38) In this study, we found a similar pathophysiology in multiple RA animal models. Elevated osteoclastic bone resorption in RA subchondral bone activated excessive amounts of TGF-β, which recruited MSCs/ osteoprogenitors to the subchondral bone marrow that were incapable of proper osteogenic differentiation.…”

Section: Discussionsupporting

confidence: 78%

Aberrant Activation of TGF-β in Subchondral Bone at the Onset of Rheumatoid Arthritis Joint Destruction

Xu¹,

Zheng²,

Bian³

et al. 2015

Journal of Bone and Mineral Research

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Rheumatoid arthritis (RA) is an autoimmune disease that often leads to joint destruction. A myriad of drugs targeting the immune abnormalities and downstream inflammatory cascades have been developed, but the joint destruction is not effectively halted. Here we report that aberrant activation of TGF-β in the subchondral bone marrow by immune response increases osteoprogenitors and uncoupled bone resorption and formation in RA mouse/rat models. Importantly, either systemic or local blockade of TGF-β activity in the subchondral bone attenuated articular cartilage degeneration in RA. Moreover, conditional deletion of TGF-β receptor II (Tgfbr2) in nestin-positive cells also effectively halted progression of RA joint destruction. Our data demonstrate that aberrant activation of TGF-β in the subchondral bone is involved at the onset of RA joint cartilage degeneration. Thus, modulation of subchondral bone TGF-β activity could be a potential therapy for RA joint destruction.

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Section: Discussionsupporting

confidence: 78%

Aberrant Activation of TGF-β in Subchondral Bone at the Onset of Rheumatoid Arthritis Joint Destruction

Xu¹,

Zheng²,

Bian³

et al. 2015

Journal of Bone and Mineral Research

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“…However, unlike the response of ATDC5 chondroprogenitors, we did not concurrently observe transcriptional enhancement of chondrocyte SOX9 with TRPV4 activation, suggesting that fully differentiated articular chondrocytes use an alternate mechanism for COL2α1 enhancement. Transforming growth factor (TGF) signaling plays an important role in cartilage development and homeostasis (53), as well as the response of other cell types to mechanical stimulation (54,55). The mechanoresponsiveness of chondrocyte TGF-β3 gene expression that preceded the regulation of the other genes measured in this study, along with its dependence on TRPV4 activity to mediate this response, represents an intriguing potential mechanism for the biophysical to biochemical transduction of mechanical loading in articular cartilage.…”

Section: Camentioning

confidence: 74%

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading

O’Conor

Leddy

Benefield

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

384

448

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Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharmacologic therapies for joint diseases. Transient receptor potential vanilloid 4 (TRPV4), a Ca 2+ -permeable osmomechano-TRP channel, is highly expressed in articular chondrocytes, and loss of TRPV4 function is associated with joint arthropathy and osteoarthritis. The goal of this study was to examine the hypothesis that TRPV4 transduces dynamic compressive loading in articular chondrocytes. We first confirmed the presence of physically induced, TRPV4-dependent intracellular Ca 2+ signaling in agarose-embedded chondrocytes, and then used this model system to study the role of TRPV4 in regulating the response of chondrocytes to dynamic compression. Inhibition of TRPV4 during dynamic loading prevented acute, mechanically mediated regulation of proanabolic and anticatabolic genes, and furthermore, blocked the loadinginduced enhancement of matrix accumulation and mechanical properties. Furthermore, chemical activation of TRPV4 by the agonist GSK1016790A in the absence of mechanical loading similarly enhanced anabolic and suppressed catabolic gene expression, and potently increased matrix biosynthesis and construct mechanical properties. These findings support the hypothesis that TRPV4-mediated Ca 2+ signaling plays a central role in the transduction of mechanical signals to support cartilage extracellular matrix maintenance and joint health. Moreover, these insights raise the possibility of therapeutically targeting TRPV4-mediated mechanotransduction for the treatment of diseases such as osteoarthritis, as well as to enhance matrix formation and functional properties of tissue-engineered cartilage as an alternative to bioreactor-based mechanical stimulation. mechanobiology | ion channel | calcium signaling | TGF-beta | tissue engineering

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“…Recent studies have also identified aberrant TGF-β signaling in bone as a key pathway in OA [127]. In the ACL transection model of OA, high doses of a TGF-β inhibitor administered systemically promoted cartilage proteoglycan loss, whereas lower doses prevented the migration and/or localization of MSCs, osteoprogenitors, and osteoblasts in the subchondral bone of operated limbs and attenuated neovascularization and cartilage loss.…”

Section: Cartilage Anabolism and Tissue Engineering Strategiesmentioning

confidence: 99%

Emerging targets in osteoarthritis therapy

Goldring

Bérenbaum

2015

Current Opinion in Pharmacology

150

124

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Osteoarthritis (OA) is a destructive joint disease in which the initiation may be attributed to direct injury and mechanical disruption of joint tissues, but the progressive changes are dependent on active cell-mediated processes that can be observed or inferred during the generally long time-course of the disease. Based on clinical observations and experimental studies, it is now recognized a that it is possible for individual patients to exhibit common sets of symptoms and structural abnormalities due to distinct pathophysiological pathways that act independently or in combination. Recent research that has focused on the underlying mechanisms involving biochemical cross talk among the cartilage, synovium, bone, and other joint tissues within a background of poorly characterized genetic factors will be addressed in this review.

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TGF-β and osteoarthritis—the good and the bad

Cited by 60 publications

References 15 publications

Aberrant Activation of TGF-β in Subchondral Bone at the Onset of Rheumatoid Arthritis Joint Destruction

Aberrant Activation of TGF-β in Subchondral Bone at the Onset of Rheumatoid Arthritis Joint Destruction

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading

Emerging targets in osteoarthritis therapy

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