Age-related changes in cartilage endogenous osteogenic protein-1 (OP-1)

Chubinskaya, Susan; Kumar, Bhavna; Merrihew, Charis; Heretis, Katherine; Rueger, David C.; Kuettner, Klaus E.

doi:10.1016/s0925-4439(02)00158-8

Cited by 78 publications

(78 citation statements)

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“…Single-nucleotide polymorphisms (SNPs) in BMP2 were found in OA patients but their functional relevance is unknown (Valdes et al 2004(Valdes et al , 2006. The expression levels of BMP7 decline with increasing age and with progression of OA (Chubinskaya et al 2002), and the expression domains of GDF5 and GDF6 expand in adult human OA articular cartilage (Erlacher et al 1998). BMP-7 possesses cartilage-protective properties by enhancing the expression of cartilage ECM and counteracting catabolic enzyme synthesis (Huch et al 1997;Im et al 2003).…”

Section: Dysregulation Of Tgf-b or Bmp Signaling In Catabolic Bone DImentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Dysregulation Of Tgf-b or Bmp Signaling In Catabolic Bone DImentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…17,18 This effect is synergistic with IGF-1, 19 and aged osteoarthritic chondrocytes still respond to BMP-7 with increased anabolic activity and viability. 12,13 Bobacz 20 and others have shown that BMP-7 improves the amount, quality, and integration of repair tissue in experimental cartilage defects. [21][22][23] Models of knee OA after mechanical injury include contusive impact applied through an arthrotomy, 24 arthroscopically, 25 or to the closed joint 26 in the rabbit, 27 dog, 26,28 sheep, 29 and horse.…”

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confidence: 97%

“…[6][7][8] Strategies that prevent cartilage degeneration in the posttraumatic knee would be very valuable. Although there is experimental evidence that this goal may be attainable, [9][10][11][12][13][14][15] recent reviews of OA treatment strategies in clinical trials concluded that definitive evidence for disease modification in OA is scant. [9][10] Prevention of OA after injury would require stimulation of repair mechanisms and promotion of an anabolic metabolism in the face of catabolic mediators such as IL-1.…”

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confidence: 99%

“…[9][10] Prevention of OA after injury would require stimulation of repair mechanisms and promotion of an anabolic metabolism in the face of catabolic mediators such as IL-1. Members of the bone morphogenetic protein (BMP) family are better known for their role in bone repair, but these proteins have well-established anabolic and anticatabolic effects in articular tissues including upregulation of chondrocyte metabolism [11][12][13][14] in the presence of IL-1 15,16 and fibronectin fragments. 17,18 This effect is synergistic with IGF-1, 19 and aged osteoarthritic chondrocytes still respond to BMP-7 with increased anabolic activity and viability.…”

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confidence: 99%

“…33 The OARSI scoring system produced a score between 0 and 24 that was the mathematical product of the lesion grade and stage. Grade (0-6) indicated depth of the lesion where lesion stage corresponds to the area of abnormal cartilage as determined by India ink staining and histological examination of multiple (12)(13)(14)(15) sections of the femoral condyle. Cartilage sulfated glycosaminoglycan (sGAG) concentration was detected by a microplate adaptation of the dimethylmethylene blue precipitation method 34 compared against standard curves prepared with chondroitin sulfate C (#C-43841, Sigma-Aldrich).…”

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BMP‐7 protects against progression of cartilage degeneration after impact injury

Hurtig

Chubinskaya

Dickey

et al. 2008

Journal Orthopaedic Research

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In vivo studies were used to characterize a model of cartilage injury leading to osteoarthritis progression in the medial femorotibial joint of sheep. In three subsequent studies, bilateral impact injuries were created and one joint received intraarticular injections of 340 mg of rhBMP-7 protein in a collagen particle carrier while the contralateral knee received the vehicle alone. Sheep were allocated to three groups that received intraarticular injections on day 0 (group A), 21 (group B), or 90 (group C) after experimental knee injury. In each group the, joints were evaluated for signs of osteoarthritis progression 90 days after the last treatment using India ink stained area, OARSI histological scoring, cartilage sGAG content, immunostaining for apoptosis (TUNEL), caspase-3, collagen degradation (Col 2 3/4C short collagen epitope), and the endogenous (pro-) form of BMP-7 protein. Knee joints that received rhBMP-7 immediately after injury had small focal lesions at the injury site that did not progress into the surrounding cartilage. Joints that received BMP-7 3 weeks after injury were improved and had limited progression compared to controls, but joints that received the protein 12 weeks after injury had no statistically significant improvement. These studies suggest that BMP-7 may be chondroprotective after traumatic injury in patients if it is administered within 3 to 4 weeks of the index injury. The mechanism of protection after sublethal injury appeared to be an increased survival of chondrocytes that are able to participate in the repair process. ß

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Antisense inhibition of osteogenic protein 1 disturbs human articular cartilage integrity

Söder

Hakimiyan

Rueger

et al. 2005

Arthritis & Rheumatism

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Objective. To delineate the role of endogenous osteogenic protein 1 (OP-1) in human articular cartilage homeostasis via the inhibition of OP-1 gene expression by antisense oligonucleotides.Methods. Human adult normal articular cartilage was obtained from the knee and ankle joints of 34 organ donors. Chondrocytes were cultured as tissue explants or isolated cells in alginate or high-density monolayers for 48 hours in the presence of OP-1 antisense or sense oligonucleotides. The effect of OP-1 antisense inhibition was evaluated by reverse transcription-polymerase chain reaction, 35 S incorporation, dimethylmethylene blue assay, histology with Safranin O staining, and immunohistochemistry with anti-proOP-1, anti-mature OP-1, and anti-aggrecan antibodies.Results. Antisense treatment inhibited OP-1 gene expression by a mean ؎ SD of 34 ؎ 12% (P < 0.01) in chondrocytes cultured in monolayers and by 77 ؎ 27% (P < 0.03) in alginate beads. The inhibition of autocrine OP-1 caused a striking decrease in aggrecan gene expression, in total proteoglycan content accumulated in cartilage matrix, and in the ability of chondrocytes to newly synthesize proteoglycans. OP-1 antisense reduced aggrecan messenger RNA expression by 42 ؎ 17% (P < 0.05) and proteoglycan synthesis by 48 ؎ 23% (P < 0.01). Histology and immunohistochemistry revealed a dramatic decrease in Safranin O staining and reduced anti-aggrecan staining (primarily in the superficial and middle cartilage layers) with OP-1 antisense treatment.Conclusion. Our results suggest that OP-1 is an important endogenous cartilage factor that regulates matrix integrity and possibly needs to be induced or up-regulated to maintain normal cartilage homeostasis. These findings confirm our hypothesis that a lack of autocrine OP-1 may lead to an elevated susceptibility of chondrocytes to the catabolic processes, thus contributing/promoting cartilage degeneration.Articular cartilage degeneration, which occurs with aging and is accelerated in osteoarthritis, is characterized by dysregulation of chondrocyte metabolism leading to imbalance between anabolism and catabolism. Growth factors, and specifically the members of the bone morphogenetic protein (BMP) family, can act as important regulators of matrix production and repair (1,2). Among these factors, osteogenic protein 1 (OP-1; or BMP-7) has received particular attention for its ability to induce matrix synthesis in adult articular cartilage (2-4).OP-1 was first purified from demineralized bone matrix and was shown to induce ectopic endochondral bone formation (5-7). OP-1 has since been identified in many other tissues of various species, including humans, mice, chickens, rabbits, goats, Drosophila, and Caenorhabditis elegans (1,2,(8)(9)(10)(11). It is synthesized as a precursor of 431 amino acids, which encode for a signal peptide, a pro-domain containing 29-292 amino acids, and a mature domain formed by residues 293-431 (12,13). We recently showed that human articular chondrocytes express endogenous OP-1 (11), which is present in carti...

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Age-related changes in cartilage endogenous osteogenic protein-1 (OP-1)

Cited by 78 publications

References 36 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

BMP‐7 protects against progression of cartilage degeneration after impact injury

Antisense inhibition of osteogenic protein 1 disturbs human articular cartilage integrity

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