Stimulation of BMP-2 expression by pro-inflammatory cytokines IL-1 and TNF-alpha in normal and osteoarthritic chondrocytes.

Abstract

BACKGROUND:

Destruction of cartilage in osteoarthritis is a direct effect of an imbalance between catabolic and anabolic activities in the tissue. While a great deal is known about catabolism, we sought to determine the biochemical basis of the anabolic activity.

METHODS:

Cartilage was isolated from normal and osteoarthritic patients and subjected to both cell and explant culture. mRNA expression levels of the growth and differentiation factors bone morphogenetic protein-2 (BMP-2), BMP-4, BMP-6, cartilage-derived morphogenetic protein-1 (CDMP-1), connective tissue growth factor (CTGF), and activin were determined. BMP-2 was localized in osteoarthritic cartilage by immunohistochemistry. To determine the mechanism of BMP-2 stimulation, chondrocytes were cultured with TGF-beta (transforming growth factor-beta), insulin-like growth factor-1 (IGF-1), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). The BMP-2 response was monitored by quantitative real-time polymerase chain reaction to ascertain mRNA levels and by Western blot analysis, BMP-2 protein quantitation, and immunohistochemistry to determine protein levels.

RESULTS:

BMP-2 was found to be up-regulated in osteoarthritic chondrocytes and cartilage. In cell culture, IL-1beta and TNF-alpha increased BMP-2 mRNA and protein levels by eightfold and fifteenfold, respectively, whereas IGF-1 and TGF-beta1 had no effect. In cartilage explant cultures, IL-1beta and TNF-alpha increased BMP-2 levels both intracellularly and extracellularly. Functional relevance was suggested by co-localization of BMP-2 and newly synthesized type-II procollagen within the same cells.

CONCLUSIONS:

BMP-2 acts as a stimulus of anabolic activities in normal and osteoarthritic chondrocytes. Furthermore, the pro-inflammatory cytokines IL-1beta and TNF-alpha, known to be present in synovium and cartilage of patients with osteoarthritis, stimulate the production of active BMP-2.

• Authors: Naoshi Fukui, Yong Zhu, William J Maloney, John Clohisy, Linda J Sandell
• Journal: The Journal of bone and joint surgery. American volume (J Bone Joint Surg Am) Vol. 85-A Suppl 3 Pg. 59-66 ( 2003) ISSN: 0021-9355 [Print] United States
• PMID: 12925611 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BMP2 protein, human
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Proteins
• Interleukin-1
• RNA, Messenger
• Transforming Growth Factor beta
• Tumor Necrosis Factor-alpha

Topics

• Aged
• Aged, 80 and over
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Proteins (genetics)
• Cartilage, Articular (cytology)
• Cell Differentiation (genetics)
• Cells, Cultured
• Chondrocytes (cytology)
• Female
• Gene Expression Regulation (immunology)
• Humans
• Interleukin-1 (physiology)
• Male
• Middle Aged
• Osteoarthritis (immunology)
• RNA, Messenger (genetics)
• Transforming Growth Factor beta
• Tumor Necrosis Factor-alpha (physiology)
• Up-Regulation (physiology)