scholarly journals BMP signaling is necessary and sufficient for osteoarthritis and a target for disease modifying therapy

2021 ◽  
Author(s):  
Akrit Pran Jaswal ◽  
Anke J Roelofs ◽  
Amaresh Kumar Singh ◽  
Bhupendra Kumar ◽  
Anna H.K. Riemen ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cartilage Degeneration ◽  
Bmp Signaling ◽  
Endochondral Bone ◽  
Local Inhibition ◽  
Adult Mice ◽  
Disease Modifying Therapy ◽  
Cartilage Differentiation ◽  
Ectopic Activation ◽  
Disease Modifying

Osteoarthritis (OA) is among the leading causes of disability across the world. Presently no effective therapy of OA is available as neither the molecular mechanism of disease pathology nor the development and maintenance of articular cartilage is well understood. During OA, articular cartilage undergoes cellular and molecular changes reminiscent of transient cartilage, which is the embryonic precursor of endochondral bone. During endochondral ossification, a precise spatio-temporally regulated WNT-BMP signaling interplay dictates differentiation of a common progenitor pool to either articular or transient cartilage fate in adjacent domains. In the embryonic context, Wnt signaling promotes articular cartilage fate while transient cartilage differentiation is critically BMP signaling dependent. Moreover, any ectopic activation of BMP signaling leads to ectopic transient cartilage differentiation at the expense of articular cartilage. In this study, we show that BMP signaling is sufficient and necessary for the pathogenesis of OA by ectopically activating BMP signaling and depleting BMP ligands in adult mice articular cartilage, respectively. Analysis of human osteoarthritic specimens demonstrated association between OA and ectopic BMP signaling in the articular cartilage. Local inhibition of BMP signaling using a potent pharmacological inhibitor LDN-193189, when administered prophylactically, resulted in delayed onset and reduced severity of OA in mice. Additionally, the same treatment afforded protection against cartilage degeneration post onset of OA in a surgical model of OA in mice. Therefore, inhibiting BMP signaling and consequent block of transient cartilage differentiation within the cells of the joint cartilage can be a possible avenue for developing a disease modifying therapy for OA.

Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis

2021 ◽  
Vol 13 (580) ◽  
pp. eaau8491 ◽  
Author(s):  
Elijah L. Carlson ◽  
Vengadeshprabhu Karuppagounder ◽  
William J. Pinamont ◽  
Natalie K. Yoshioka ◽  
Adeel Ahmad ◽  
...  
Keyword(s):  
G Protein ◽  
Cartilage Regeneration ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Joint Disease ◽  
G Protein Coupled Receptor ◽  
Disease Modifying Therapy ◽  
Disease Modifying ◽  
Disease Modifying Treatment ◽  
G Protein Coupled

Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein–coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein–coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)–approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.

scholarly journals Aggrecan Hypomorphism Compromises Articular Cartilage Biomechanical Properties and Is Associated with Increased Incidence of Spontaneous Osteoarthritis

2019 ◽  
Vol 20 (5) ◽  
pp. 1008 ◽  
Author(s):  
Paolo Alberton ◽  
Hans Dugonitsch ◽  
Bastian Hartmann ◽  
Ping Li ◽  
Zsuzsanna Farkas ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cartilage Degeneration ◽  
Biomechanical Properties ◽  
Cartilage Tissue ◽  
Gene Encoding ◽  
Adult Mice ◽  
Skeletal Malformations ◽  
Wide Range ◽  
Normal Expression ◽  
Cartilage Erosion

The gene encoding the proteoglycan aggrecan (Agc1) is abundantly expressed in cartilage during development and adulthood, and the loss or diminished deposition of the protein results in a wide range of skeletal malformations. Furthermore, aggrecan degradation is a hallmark of cartilage degeneration occurring in osteoarthritis. In the present study, we investigated the consequences of a partial loss of aggrecan in the postnatal skeleton and in the articular cartilage of adult mice. We took advantage of the previously described Agc1tm(IRES-CreERT2) mouse line, which allows for conditional and timely-regulated deletion of floxed, cartilage-expressed genes. As previously reported, the introduction of the CreERT2 cassette in the 3’UTR causes a disruption of the normal expression of Agc1 resulting in a hypomorphic deposition of the protein. In homozygous mice, we observed a dwarf phenotype, which persisted throughout adulthood supporting the evidence that reduced aggrecan amount impairs skeletal growth. Homozygous mice exhibited reduced proteoglycan staining of the articular cartilage at 6 and 12 months of age, increased stiffening of the extracellular matrix at six months, and developed severe cartilage erosion by 12 months. The osteoarthritis in the hypomorph mice was not accompanied by increased expression of catabolic enzymes and matrix degradation neoepitopes. These findings suggest that the degeneration found in homozygous mice is likely due to the compromised mechanical properties of the cartilage tissue upon aggrecan reduction.

scholarly journals Precise spatial restriction of BMP signaling is essential for articular cartilage differentiation

Development ◽  
2015 ◽  
Vol 142 (6) ◽  
pp. 1169-1179 ◽  
Author(s):  
A. Ray ◽  
P. N. P. Singh ◽  
M. L. Sohaskey ◽  
R. M. Harland ◽  
A. Bandyopadhyay
Keyword(s):  
Articular Cartilage ◽  
Bmp Signaling ◽  
Cartilage Differentiation

scholarly journals Mechanical stress determines the configuration of TGFβ activation in articular cartilage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gehua Zhen ◽  
Qiaoyue Guo ◽  
Yusheng Li ◽  
Chuanlong Wu ◽  
Shouan Zhu ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Mechanical Stress ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cartilage Degeneration ◽  
Cell Stiffness ◽  
Disease Modifying Therapy ◽  
High Level ◽  
Contractile Forces ◽  
Consequent Increase

AbstractOur incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. The functional relationship between subchondral bone (SB) and articular cartilage (AC) is unclear. Here, we found that the changes of SB architecture altered the distribution of mechanical stress on AC. Importantly, the latter is well aligned with the pattern of transforming growth factor beta (TGFβ) activity in AC, which is essential in the regulation of AC homeostasis. Specifically, TGFβ activity is concentrated in the areas of AC with high mechanical stress. A high level of TGFβ disrupts the cartilage homeostasis and impairs the metabolic activity of chondrocytes. Mechanical stress stimulates talin-centered cytoskeletal reorganization and the consequent increase of cell contractile forces and cell stiffness of chondrocytes, which triggers αV integrin–mediated TGFβ activation. Knockout of αV integrin in chondrocytes reversed the alteration of TGFβ activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. Thus, SB structure determines the patterns of mechanical stress and the configuration of TGFβ activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis.

The Effect of Total Meniscectomy versus Caudal Pole Hemimeniscectomy on the Stifle Joint of the Sheep

1999 ◽  
Vol 12 (02) ◽  
pp. 56-63 ◽  
Author(s):  
C. R. Bellenger ◽  
P. Ghosh ◽  
Y. Numata ◽  
C. Little ◽  
D. S. Simpson
Keyword(s):  
Tissue Culture ◽  
Articular Cartilage ◽  
Fibrous Tissue ◽  
Cartilage Degeneration ◽  
Medial Compartment ◽  
Proteoglycan Synthesis ◽  
Stifle Joint ◽  
Medial Meniscectomy ◽  
Tibial Condyle ◽  
Articular Cartilage Degeneration

SummaryTotal medial meniscectomy and caudal pole hemimeniscectomy were performed on the stifle joints of twelve sheep. The two forms of meniscectomy produced a comparable degree of postoperative lameness that resolved within two weeks of the operations. After six months the sheep were euthanatised and the stifle joints examined. Fibrous tissue that replaced the excised meniscus in the total meniscectomy group did not cover as much of the medial tibial condyle as the residual cranial pole and caudal fibrous tissue observed following hemimeniscectomy. The articular cartilage from different regions within the joints was examined for gross and histological evidence of degeneration. Analyses of the articular cartilage for water content, glycosaminoglycan composition and DNA content were performed. The proteoglycan synthesis and release from explanted articular cartilage samples in tissue culture were also measured. There were significant pathological changes in the medial compartment of all meniscectomised joints. The degree of articular cartilage degeneration that was observed following total meniscectomy and caudal pole meniscectomy was similar. Caudal pole hemimeniscectomy, involving transection of the meniscus, causes the same degree of degeneration of the stifle joint that occurs following total meniscectomy.The effect of total medial meniscectomy versus caudal pole hemimeniscectomy on the stifle joint of sheep was studied experimentally. Six months after the operations gross pathology, histopathology, cartilage biochemical analysis and the rate of proteoglycan synthesis in tissue culture were used to compare the articular cartilage harvested from the meniscectomised joints. Degeneration of the articular cartilage from the medial compartment of the joints was present in both of the groups. Caudal pole hemimeniscectomy induces a comparable degree of articular cartilage degeneration to total medial meniscectomy in the sheep stifle joint.

MOLECULAR CONTROL OF ARTICULAR CARTILAGE DEGENERATION BY TRANSFORMING GROWTH FACTOR ALPHA

2008 ◽  
Vol 31 (4) ◽  
pp. 2
Author(s):  
Tom Appleton ◽  
Shirine Usmani ◽  
John Mort ◽  
Frank Beier
Keyword(s):  
Gene Expression ◽  
Articular Cartilage ◽  
Growth Factor ◽  
P38 Mapk ◽  
Transforming Growth Factor ◽  
Cartilage Degeneration ◽  
Signalling Pathways ◽  
Transforming Growth Factor Alpha ◽  
Factor Alpha ◽  
Articular Cartilage Degeneration

Background: Articular cartilage degeneration is a hallmark of osteoarthritis (OA). We previously identified increased expression of transforming growth factor alpha (TGF?) and chemokine (C-C motif) ligand 2 (CCL2) in articular cartilage from a rat modelof OA (1,2). We subsequently reported that TGF? signalling modified chondrocyte cytoskeletal organization, increased catabolic and decreased anabolic gene expression and suppressed Sox9. Due to other roles in chondrocytes, we hypothesized that the effects ofTGF? on chondrocytes are mediated by Rho/ROCK and MEK/ERK signaling pathways. Methods: Primary cultures of chondrocytes and articularosteochondral explants were treated with pharmacological inhibitors of MEK1/2(U0126), ROCK (Y27632), Rho (C3), p38 MAPK (SB202190) and PI3K (LY294002) to elucidate pathway involvement. Results: Using G-LISA we determined that stimulation of primary chondrocytes with TGF? activates RhoA. Reciprocally, inhibition of RhoA/ROCK but not other signalling pathways prevents modification of the actin cytoskeleton in responseto TGF?. Inhibition of MEK/ERKsignaling rescued suppression of anabolic gene expression by TGF? including SOX9 mRNA and protein levels. Inhibition of MEK/ERK, Rho/ROCK, p38 MAPK and PI3K signalling pathways differentially controlled the induction of MMP13 and TNF? gene expression. TGF? also induced expression of CCL2 specifically through MEK/ERK activation. In turn, CCL2 treatment induced the expression of MMP3 and TNF?. Finally, we assessed cartilage degradation by immunohistochemical detection of type II collagen cleavage fragments generated by MMPs. Blockade of RhoA/ROCK and MEK/ERK signalling pathways reduced the generation of type IIcollagen cleavage fragments in response to TGF? stimulation. Conclusions: Rho/ROCK signalling mediates TGF?-induced changes inchondrocyte morphology, while MEK/ERK signalling mediates the suppression ofSox9 and its target genes, and CCL2 expression. CCL2, in turn, induces the expression of MMP3 and TNF?, two potent catabolic factors known to be involved in OA. These pathways may represent strategic targets for interventional approaches to treating cartilage degeneration in osteoarthritis. References: 1. Appleton CTG et al. Arthritis Rheum 2007;56:1854-68. 2. Appleton CTG et al. Arthritis Rheum 2007; 56:3693-705.

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