Over 58 million US adults have arthritis, and there are over 100 types of arthritis with different causes. Multiple forms of arthritis are thought to be caused by a fault in the immune system that causes the body to attack its own tissues in the joints, such as with Rheumatoid arthritis (RA) and Lupus. ^[1] This kind of autoimmune-based arthritis may be inherited genetically. Other forms of arthritis can be caused by problems with the immune system or by a metabolic condition, such as gout. Osteoarthritis (OA) is the most common form of arthritis, affecting millions of people worldwide. As the major aggrecanase-degrading articular cartilage matrix, ADAMTS5, has been regarded as a potential target for OA treatment. Herein, we provide information on ADAMTS5 gene research and the latest insights into OA treatment strategies.

Overview of ADAMTS5 Gene

ADAMTS5 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 5) is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme contains two C-terminal TS motifs and functions as an aggrecanase that cleaves aggrecan, a major proteoglycan of cartilage, and may mediate cartilage destruction in osteoarthritis. ^[2]

Protein Function

ADAMTS-5 is a metalloproteinase that plays an important role in connective tissue organization, development, inflammation and cell migration. In previous studies, Nakada M et al. have demonstrated that ADAMTS-5 is capable of digesting brevican in an identical pattern to ADAMTS-4, and is overexpressed by glioblastoma cells. Their data suggest the possible implications of ADAMTS-5 in human glioblastoma cell invasion. ^[3] ADAMTS5 Plays an important role for T-lymphocyte migration from draining lymph nodes following viral infection.

Figure 2. AlphaFold structure prediction (ADAMTS5) (Source: Uniprot)

Studies in vitro, ex vivo and in vivo have validated ADAMTS-5 as a target in osteoarthritis (OA). For this reason, it attracted the interest of many research groups aiming to develop a therapeutic treatment for OA patients. How much do you know about osteoarthritis? Check out the details below.

Osteoarthritis

Arthritis is the swelling and tenderness of one or more joints. The main symptoms of arthritis are joint pain and stiffness, which typically worsen with age. The most common types of arthritis are osteoarthritis and rheumatoid arthritis.

Osteoarthritis causes cartilage — the hard, slippery tissue that covers the ends of bones where they form a joint — to break down. Rheumatoid arthritis is a disease in which the immune system attacks the joints, beginning with the lining of joints.

Gout is another type of arthritis caused by the buildup of uric acid crystals in the joint, which forms when there's too much uric acid in your blood. Infections or underlying diseases, such as psoriasis or lupus, can cause other types of arthritis.

Figure 1 – The stages of osteoarthritis, as demonstrated in the knee joint ^[4]

Treatments vary depending on the type of arthritis. The main goals of arthritis treatments are to reduce symptoms and improve quality of life.

Symptoms

Osteoarthritis symptoms usually develop slowly and get worse over time. Signs and symptoms of osteoarthritis include:

• Pain. Affected joints may hurt or even be injured during or after exercise.

• Rigidity. Joint stiffness may be most noticeable after waking or after inactivity.

• Tenderness. Joints may feel tender when light pressure is applied on or near them.

• Loss of flexibility. It may not be possible to move the joint through the full range of motion.

• Grating sensation. When using the joint, a harsh feeling may be felt and a popping or crackling sound may be heard.

• Bone spur. These extra bones, which feel like lumps, can form around the affected joint.

• Swelling. This can be caused by inflammation of the soft tissue around the joint.

To Be Continued: Mouse Models of ADAMTS5

On the 21st anniversary of the discovery of ADAMTS-5, this article looks at its deleterious effects in development of OA. How did the researchers discover the mechanism of action of ADAMTS-5? In the next article, we will describe applied research of the ADAMTS-5 mouse model, including the challenges and emerging trends in ADAMTS-5 research.

>>Learn more: Adamts5 Mice and New Research Progress

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Reference:

[1]https://www.cdc.gov/arthritis/basics/osteoarthritis.htm

[2]https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADAMTS5

[3] Nakada M, Miyamori H, Kita D, Takahashi T, Yamashita J, Sato H, Miura R, Yamaguchi Y, Okada Y. Human glioblastomas overexpress ADAMTS-5 that degrades brevican. Acta Neuropathol. 2005 Sep;110(3):239-46. doi: 10.1007/s00401-005-1032-6. Epub 2005 Aug 30. PMID: 16133547.

[4]https://teachmesurgery.com/orthopaedic/principles/osteoarthritis/