The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitin-induced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.

Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury.

1. YKL-40 In a search of new bone proteins, the glycoprotein YKL-40 was identified in 1989 to be secreted in vitro in large amount by the human osteosarcoma cell line MG63. The protein was named YKL-40 based on its three N-terminal aminoacids Tyrosine (Y), Lysine (K) and Leucine (L) and its molecular mass of 40 kDa (Johansen et al. 1992). This protein was later found to be similar to a protein secreted by differentiated smooth muscle cells from swine explants of the thoracic aorta (Millis et al. 1985), to a protein isolated from the whey protein secretions of bovine mammary secretions during the nonlactating period (Rejman et al. 1988), and to a heparin binding protein secreted by human synovial cells (Nyirkos et al. 1990). In the last few years there has been a growing number of publications concerning YKL-40 and the “Story about YKL-40” has probably just started. The protein has several names: “YKL-40” (Johansen et al. 1992), “Human Cartilage glycoprotein-39 (HC gp39)” (Hakala et al. 1993), “Breast regressing protein 39 Kd (brp-39)” (Morrison et al. 1994), “38-kDa heparin-binding glycoprotein (gp38k)” (Shackelton et al. 1995), “Chitinase-3-like-1 (CHI3L1)” (Rehli et al. 1997), “Chondrex” (Harvey et al. 1998), and “40 kDa mammary gland protein (MGP-40)” (Mohanty et al. 2003). Hopefully, there will in the future be consensus of its name. In this thesis the protein is named YKL-40.

Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer

YKL-40, a member of the "mammalian chitinase-like proteins," is expressed and secreted by several types of solid tumors. The exact function of YKL-40 in cancer diseases is unknown and is an important objective of future studies. YKL-40 exhibits growth factor activity for cells involved in tissue remodeling processes. YKL-40 may have a role in cancer cell proliferation, survival, and invasiveness, in the inflammatory process around the tumor, angiogenesis, and remodeling of the extracellular matrix. YKL-40 is neither organ- nor tumor-specific. However, the present retrospective clinical studies of patients with eight different types of primary or advanced solid tumors suggest that serum concentration of YKL-40 may be a new biomarker in cancer patients used as a "prognosticator." Elevated serum YKL-40 is found in a subgroup of patients with different types of solid tumors, including several types of adenocarcinomas, small cell lung carcinoma, glioblastoma, and melanoma. The highest serum YKL-40 is detected in patients with advanced cancer and with the poorest prognosis. In many cases, serum YKL-40 provides independent information of survival. Serum YKL-40 cannot be used as a single screening test for cancer. The use of serum YKL-40 has not received Food and Drug Administration approval for use as a biomarker for cancer or any other disease. Large multicenter retrospective and prospective studies of patients with different types of cancer are required to determine: (a) if serum YKL-40 is a useful prognostic cancer biomarker, (b) if serum YKL-40 can be of value in monitoring patients with cancer in order to provide information about metastases before these are detected by routine methods, and (c) if serum YKL-40 can be useful for screening of cancer together with a panel of other cancer biomarkers and imaging techniques.

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Serum YKL-40, a new prognostic biomarker in cancer patients?

Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma

Substantial evidence supports a role of chronic subclinical inflammation and activation of the innate immune system in the pathogenesis of insulin resistance and endothelial dysfunction and the development of type 2 diabetes (T2D) and atherosclerosis. Several proinflammatory cytokines, acute phase-reactants and cell adhesion molecules play a pivotal role in this chronic subclinical inflammation but a comprehensive understanding of the interrelations of these molecules is still needed. YKL-40 is a new inflammatory marker with relation to acute and chronic inflammation as well as cancer. It is secreted in vitro from a variety of human cells, including vascular smooth muscle cells (VSMCs), activated macrophages and macrophages during late stages of differentiation and is found in vivo in subpopulations of macrophages in tissues with inflammation and extracellular tissue remodelling, such as macrophages in atherosclerotic plaques. YKL-40 promotes chemotaxis, cell attachment and migration of VSMCs and the formation of branching tubules suggesting that YKL-40 plays a role in angiogenesis. Latest studies reveal that YKL-40 is elevated in patients with T2D and is related to insulin resistance. This article reviews the studies of YKL-40 with focus on a possible role of YKL-40 in insulin resistance, endothelial dysfunction and atherosclerosis.

YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis.

http://labs.biology.ucsd.edu/pprice/YKL-40%20papers/Volck%202001.pdf

Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology

Objective To identify predictors of flare in a 2-year follow-up study of patients with rheumatoid arthritis (RA) in sustained clinical remission tapering towards withdrawal of biological disease-modifying anti-rheumatic drugs (bDMARDs). Methods Sustained clinical remission was defined as Disease Activity Score for 28 joints (DAS28)-C reactive protein (CRP) ≤2.6 without radiographic progression for >1 year. bDMARDs were tapered according to a mandatory clinical guideline to two-thirds of standard dose at baseline, half of dose at week 16 and discontinuation at week 32. Prospective assessments for 2 years included clinical evaluation, conventional radiography, ultrasound and MRI for signs of inflammation and bone changes. Flare was defined as DAS28-CRP ≥2.6 with ∆DAS28-CRP ≥1.2 from baseline. Baseline predictors of flare were assessed by logistic regression analyses. Results Of 142 included patients, 121 (85%) flared during follow-up of which 86% regained remission within 24 weeks after flare. Patients that flared were more often rheumatoid factor positive, had tried more bDMARDs and had higher baseline ultrasound synovitis sum scores than those not flaring. For patients on standard dose, predictors of flare within 16 weeks after reduction to two-thirds of standard dose were baseline MRI-osteitis (OR 1.16; 95% CI 1.03 to 1.33; p=0.014), gender (female) (OR 6.71; 95% CI 1.68 to 46.12; p=0.005) and disease duration (OR 1.06; 95% CI 1.01 to 1.11; p=0.020). Baseline predictors for flare within 2 years were ultrasound grey scale synovitis sum score (OR 1.19; 95% CI 1.02 to 1.44; p=0.020) and number of previous bDMARDs (OR 4.07; 95% CI 1.35 to 24.72; p=0.007). Conclusion The majority of real-world patients with RA tapering bDMARDs flared during tapering, with the majority regaining remission after stepwise dose increase. Demographic and imaging parameters (MR-osteitis/ultrasound greyscale synovitis) were independent predictors of immediate flare and flare overall and may be of importance for clinical decision-making in patients eligible for tapering.

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K. Ostergaard

Papers

Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology

Flare during tapering of biological DMARDs in patients with rheumatoid arthritis in routine care: characteristics and predictors