Growth factors in cartilage biology and osteoarthritis

Cartilage is a flexible connective tissue which can rapidly grow and which is specialized to absorb and resist compression. The perichondrium, a vascularized layer, surrounds the tissue which does not contain any blood vessels of its own. Therefore nutrients and waste material have to be able to diffuse through the cartilage tissue. A thin layer of smooth hyaline cartilage (the so called articular cartilage) covering the joint surfaces of the bone, does not have any perichondrium though. Articular cartilage is protected by synovial fluid, a nutritive and lubricating medium.

Chondrocytes, enclosed in Gelenkentzündungen bei Arthroseso-called lacunae (small cavities) and often appearing in groups of 2, 4, or 6 cells only make up 10-20% of the cartilage volume, the remainder is filled with highly hydrated extracellular material.

Most of the bones are derived from cartilage templates – a process called endochondral ossification. It involves the destruction and removal of cartilage and formation of bone in the space formerly occupied by cartilage tissue – an orchestrated process in which higly vascularized bone tissue replaces avascular cartilage tissue.

Osteoarthritis (OA), a chronic inflammatory disease, is characterized by a degeneration of articular cartilage in synovial joints. It represents the main cause of disability for individuals over the age of 65. Risk factors include aging, obesity and overuse or abuse of joints. The exact biological mechanism for the onset of OA is not yet clearly defined, but it is generally accepted that OA – at least in the advanced phase of the disease – results from reactivation of endochondral ossification.

Factors involved in cartilage biology and endochondral ossification

Bone morphogenetic proteins (BMPs)

BMPs are signaling proteins that can be linked to a variety of developmental processes. More than 30 members of the family are known. Their functionality is reached by proteolytic cleavage of biologically inactive precursor proteins which results in dimers of two 12-16 kDa proteins linked through a disulfide bond. Among various biological functions, BMPs play crucial roles in the development, growth and repair of bone and cartilage by stimulating cellular proliferation and differentiation (1).

  • BMP-10 plays a crucial role in the development of the embryonic heart by acting to stimulate and maintain cardiomyocyte proliferation. BMP-10 is structurally related to BMP-9, and both can inhibit endothelial cell proliferation and migration.
  • BMP-13 is expressed in hypertrophic chondrocytes during embryonic development of long bones. Continued postnatal expression of BMP-13 in articular cartilage suggests that it plays a regulatory role in the growth and maintenance of articular cartilage.
  • BMP-2 is a potent osteoinductive cytokine, capable of inducing bone and cartilage formation in association with osteoconductive carriers such as collagen and synthetic hydroxyapatite. In addition to its osteogenic activity, BMP-2 plays an important role in cardiac morphogenesis, and is expressed in a variety of tissues, including lung, spleen, brain, liver, prostate, ovary and small intestine.
  • BMP-4 is involved in the development and maintenance of bone and cartilage. Reduced expression of BMP-4 is associated with a number of bone diseases, including the heritable disorder Fibrodysplasia Ossificans Progressiva. (E.coli, HeLa)
  • BMP-5 is expressed in the nervous system, lungs and liver. It is a known regulator for dendritic growth in sympathetic neurons.
  • BMP-6 is abnormally expressed in breast cancer cell lines, however, its function in promoting breast cancer development is unknown.
  • BMP-7, also known as osteogenic protein-1 or OP-1, is a potent bone inducing agent, which in the presence of an appropriate osteoconductive carrier (e.g. collagen sponge or synthetic hydroxyapatite) can be used in the treatment of bone defects.
  • GDF-5 is expressed in long bones during embryonic development and postnatally in articular cartilage.

DKK-1

DKK-1 is a member of the DKK protein family.  It is a secreted protein with two cysteine rich regions and is involved in embryonic development through its inhibition of the WNT signaling pathway. Elevated levels of DKK-1 in bone marrow, plasma and peripheral blood is associated with the presence of osteolytic bone lesions in patients with multiple myeloma. DKK-1 expression in chondrocytes has been shown to inhibit experimental osteoarthritic cartilage destruction in mice (2)

IL-1ß and TNF-alpha

Molecular destruction of the cartilage matrix is mainly driven by an increased activity of partly identified proteases: matrix metalloproteinases (MMPs) and aggrecanases of the ADAMTS-family. These enzymes are induced by catabolic cytokines such as IL-1 or TNF α. (1).

  • Human IL-1 beta : IL-1β is a proinflammatory cytokine produced in a variety of cells including monocytes, tissue macrophages, keratinocytes and other epithelial cells. These cytokines have a broad range of activities including, stimulation of thymocyte proliferation, by inducing IL-2 release, B-cell maturation and proliferation, mitogenic FGF-like activity and the ability to stimulate the release of prostaglandin and collagenase from synovial cells.
  • Murine  IL-1 beta / Rat IL-1 beta: IL-1β is a proinflammatory cytokine produced in a variety of cells including monocytes, tissue macrophages, keratinocytes and other epithelial cells.

Fibroblast Growth Factors (FGF)

The Fibroblast Growth Factors (FGFs) constitute a large family of proteins involved in many aspects of development including cell proliferation, growth, and differentiation. They regulate on several cell types diverse physiologic functions like angiogenesis, cell growth, pattern formation, embryonic development, metabolic regulation, cell migration, neurotrophic effects, and tissue repair. Family members have been implicated in several disorders of bone growth, as well as in tumor formation and progression. FGF-2, FGF-18, and FGF-8, have been implicated as contributing factors in cartilage homeostasis (3).

  • FGF Basic:  FGF-basic is one of 23 known members of the FGF family. Proteins of this family play a central role during prenatal development and postnatal growth and regeneration of a variety of tissues, by promoting cellular proliferation and differentiation. You can find this factor for Human, Rat and Mouse.
  • FGF-18 : FGF-18 is a heparin binding growth factor that belongs to the FGF family. Proteins of this family play a central role during prenatal development and postnatal growth and regeneration of a variety of tissues, by promoting cellular proliferation and differentiation. FGF-18 is an essential regulator of long bone and calvarial development.
  • FG-8: FGF-8 (FGF-8b) is a heparin binding growth factor belonging to the FGF family. Proteins of this family play a central role during prenatal development and postnatal growth and regeneration of a variety of tissues, by promoting cellular proliferation and differentiation.

Gremlin, Follistatin and Noggin

BMP antagonists like Noggin (Human, Mouse), Follistatin and Gremlin have been described in normal and early osteoarthritic cartilage (4,5).

Parathyroid hormone-related protein (PTHrP)

Indian Hedgehog (Ihh) and PTHrP play significant roles in coordinating the transition of growth-plate chondrocytes to hypertrophy. This results in balancing the growth and ossification of skeletal elements (6).

Sonic Hedgehog (SHH)

SHH (Human, Mouse) and FGF-8 (see above) have been reported to exhibit strong synergistic effects on chondrogenesis in vitro. These factors are sufficient to promote outgrowth and chondrogenesis in vivo (7).

TGF-beta

TGF-beta has been reported as a factor playing a critical role in the development, growth, maintenance and repair of articular cartilage. Deregulation of its signaling and responses could be linked to osteoarthritis (OA) (8).

  • TGF-β1 is the most abundant isoform secreted by almost every cell type. It was originally identified for its ability to induce phenotypic transformation of fibroblasts and recently it has been implicated in the formation of skin tumors.
  • TGF-β2 has been shown to exert suppressive effects on IL-2 dependent T-cell growth, and may also have an autocrine function in enhancing tumor growth by suppressing immuno-surveillance of tumor development.
  • The physiological role of TGF-β3 is still unknown but its expression pattern suggests a role in the regulation of certain development processes.
References:
1. Aigner et al. European Cells and Materials 12, 2006, p 49-56
2. Oh, H. Et al., Arthritis Rheum. 64 (8), 2012, p 2568-78
3. Ellman et al., J Cell Biochem 114 (4), 2013, p 735-42
4. Tardif et al., Osteoarthritis Cartilage 17 (2), 2009, p 263-70
5. Brunet et al, Science 280 (5368), 1998, p 1455-7
6. Mak et al., Development 135, 2008, p 1947-56
7. Abzhanov and Tabin, Dev Biol 273, 2004, p 134-48
8. Finnson et al., Front Biosci (Schol Ed), 4, 2012, 251-68

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