Procollagen type I N-terminal propeptide (PINP) is a marker for fibrogenesis in bile duct ligation-induced fibrosis in rats

Abstract

BackgroundFibrosis can be described as the excess deposition of extracellular matrix (ECM) components, such as collagens and proteoglycans. Fibrosis of the liver, which eventually leads to cirrhosis, is a major global health problem. Being able to measure fibrosis progression may enable timely preventative intervention. The aim of the current study was to investigate the utility of serum procollagen type I N-terminal propeptide (PINP) as a marker of hepatic fibrosis, as distinct from bone formation, during three different periods of fibrosis development following hepatic injury induced by bile duct ligation (BDL) in rats.MethodsBDL was performed on 30 female Sprague-Dawley rats aged 6 months, and sham operations on 30 controls. Animals were killed after 14, 28, or 35 days. The extent of liver fibrosis was evaluated by quantitative histology after Sirus Red staining. Levels of serum PINP and osteocalcin (a marker solely for osteoblastic bone formation) were determined using ELISA at baseline and post termination.ResultsCollagen formation increased by 30% compared to 3% in sham-operated animals (P < 0.0001). PINP levels increased significantly in all BDL groups compared with baseline (14 days: baseline 13.9 ng/ml, termination 17.7 ng/ml, P = 0.047; 28 days: baseline 17.9 ng/ml, termination 26.2 ng/ml, P = 0.005; 35 days: baseline 18.0 ng/ml, termination 27.4 ng/ml P = 0.015, an increase of 52%). PINP levels did not change from baseline in the sham-operated rats, indicating that the increased PINP levels were due to hepatic injury. The bone-specific marker, osteocalcin, did not increase in either BDL or sham-operated rats. PINP measured in serum correlated to the extent of liver fibrosis as evaluated by quantitative histology (R2 = 0.42, P < 0.001).ConclusionPINP was associated with the development of liver fibrosis, but not bone formation, in mature rats subjected to BDL. Thus, PINP may be useful in studying the pathogenesis of liver fibrosis. However, caution should be applied when interpreting PINP levels in other disease states.

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

“…Fibrosis may begin in response to various acute or chronic stimuli, including infections, autoimmune reactions, toxins, radiation, and mechanical injury. 144 The pathogenic process driving fibrogenesis is believed to be a dynamic series of events involving complex cellular and molecular mechanisms evolving from the acute or chronic activation of tissue repair that follows repeated tissue injury, 5 In the case of liver fibrosis, these stimuli give rise to a series of events that involve several cell types working in synergy toward irreversible damage of the liver. 145 Identification and characterization of the cell types and the different mediators involved in liver fibrogenesis have expanded significantly during recent years.…”

“…A range of serological assessments have been developed to investigate some of the key structural proteins of the ECM (Table 3). 56,60,129,144,[196][197][198][199][200]217,274,276,278,311,314,[331][332][333][334][335][336][337][338][339][340][341][342][343][344][345][346][347] Measurement of these proteins may provide key information in clinical settings on the tissue turnover profile, and thereby assists in patient diagnosis, in identification of those patients in most need of treatment, and finally, in monitoring of clinical efficacy of interventions. These technologies may also be used in preclinical settings, in ex vivo and in vitro cultures, to determine the molecular mode of action in the assembly and maintenance of the matrix.…”

“…atherosclerosis (type I and III collagens, titin and versican) 217 . various fibrotic diseases including liver (type I, III, IV, V, VI collagens and biglycan), [59][60][61]144,196,197,199,200,218 lung (elastin, type I, III, and V collagen), 74,[220][221][222][223][224][225][226][227][228][229][230][231][232] and kidney. 233 Key lessons on the importance of the structural components of the matrix may be harvested from the genetic mutations that lead to pathologies.…”

Biochemical Markers of Bone Resorption and Hormonal Regulation of Bone Metabolism Following Liver Transplantation

“…У реципиентов после ОТП большинство исследователей анализи-руют изменения продуктов деградации коллагена 1-го типа, определяемые в моче или в сыворотке крови [4,9,11,17]. Вместе с тем имеются данные, что при патологических условиях в печени акти-визируются процессы отложения неспецифиче-ских фибриллярных коллагенов 1, 3 и 5-го типов [18,33], и следовательно, деградация некостного коллагена может явиться причиной завышенной оценки деградации костного коллагена 1-го типа, в частности бета-изомера С-терминального тело-пептида коллагена 1-го типа (бета-кросслапсов). В последнее время появились работы о высокой прогностической значимости сывороточной кост-ной фракции 5б тартрат-резистентной кислой фос-фатазы (КТРКФ-5б) -маркера остеокластической активности, который имеет низкую дневную ва-риабельность и не накапливается в циркулирую-щей крови в случае почечной или печеночной па-тологии [23].…”

Rheumatoid Arthritis: A Case for Personalized Health Care?

“…The metabolism of this ECM molecule may be accessed through 4 different analytes (N-propeptide of type I collagen [PINP], CTX-I, C1M, and ICTP), each providing distinct and unique information. PINP, which is released during protein synthesis, is the most used marker of bone formations, albeit it is also associated with fibro-genesis (40,41). CTX-I is a standard bone resorption marker and a measure of the osteoclast-specific protease cathepsin K destruction of type I collage (42).…”