Defects of type I procollagen metabolism correlated with decrease of prolidase activity in a case of lethal osteogenesis imperfecta

Abstract

We have studied the structure and metabolism of type I procollagen in a case of perinatal lethal osteogenesis imperfecta (OI) type II. Cultured skin fibroblasts from the proband synthesized both normal and abnormal forms of type I procollagen. Some abnormal, overmodified molecules were secreted by OI cells, although less efficiently than normal molecules from control cells. The OI fibroblasts accumulated large amounts of abnormal proa1(I) and proa2(I) chains intracellularly. The extracellular collagenolytic activity was decreased compared to control cells. Furthermore, OI cells produced less type I procollagen and demonstrated lower capacity to synthesize DNA than control cells. We have found that in contrast to prolinase activity, the activity of prolidase (an enzyme essential for collagen synthesis and cell growth) is also significantly reduced in OI cells. No differences were found in the amount of the enzyme protein recovered from both the OI and control cells. However, we found that expressions of b1 integrin and insulin-like growth factor-I receptor (receptors known to play an important role in up regulation of prolidase activity) were decreased in OI cells compared to control cells. The decrease in prolidase activity may provide an important mechanism of altered cell growth and collagen metabolism involved in producing the perinatal lethal form of the OI phenotype.Keywords: collagen; prolidase; osteogenesis imperfecta.Osteogenesis imperfecta (OI) is an autosomal dominant disorder associated with defects in the synthesis or structure of type I collagen, the major protein of bone and skin [1,2]. It is a heterogeneous disease with variable clinical manifestations including multiple fractures, deafness, blue sclerae, laxity of joints and dentinogenesis imperfecta. The Sillence classification using radiographic and clinical criteria, defines four main types of OI [3]. The mildest and most common form is type I of OI, and the most severe form is the perinatal lethal type II.More than 90% of OI cases are due to heterozygosity for mutations in the structural genes for type I collagen: COL1A1 or COL1A2. The most common defects are point mutations with the remainder comprising null alleles, exon skipping, deletions, insertions and frameshift mutations.Mutations that produce only quantitative decrease in the synthesis of type I procollagen result in a mild OI phenotype [4,5]. More severe OI phenotypes are due to mutations that result in the synthesis and secretion of structurally abnormal type I procollagen into the extracellular matrix [6,7].The structural defects result in abnormalities of collagen metabolism including: delayed or defective self-assembly of procollagen heterotrimers [8,9], post-translational overmodification of lysine and hydroxylysine residues [10,11], decreased thermal stability of procollagen trimers [12,13], increased susceptibility of trimers to specific proteases [13], decreased secretion of procollagen by skin fibroblasts [14] and defective extracellular processing of type I procollagen [15...

The role of emerging techniques in the investigation of prolidase deficiency: From diagnosis to the development of a possible therapeutical approach

“…In our opinion this view is short-sighted since by researching this disease the opportunity increases to unlock the mystery of cell metabolism. For instance, in a series of interesting papers published by Palka et al, the levels of prolidase activity have been shown to correlate with collagen synthesis in Osteogenesis imperfecta [52,53], in pancreatic diseases [54] or in lung carcinoma planoepitheliale [55] and breast cancer MCF-7 cells [56][57][58]. These and other papers clearly indicate how important is the role of prolidase in collagen metabolism.…”

Stimulation of collagen biosynthesis by flavonoid glycosides in skin fibroblasts of osteogenesis imperfecta type I and the potential mechanism of their action

“…Compound [7] was a less effective stimulator since it increased collagen synthesis by 63% of the control. It is known that disturbances in proline and lysine hydroxylation as well as lysine glycosylation of procollagen chains result in retarded folding and secretion, and consequently in increased intracellular degradation of procollagen (2,3,27,28). Secretion of procollagen into media by the compound-treated cells was normal or slightly increased which suggests that they did not affect either modification or folding of procollagen chains.…”

Serum prolidase activity and oxidative–antioxidative status in Legg–Calve–Perthes disease

“…Some studies showed that there is a relationship between serum prolidase concentrations and bone metabolism [4,7,10,13,14]. Verit et al [4] showed that serum levels of prolidase were significantly elevated in postmenopausal osteoporotic women compared with premenopausal women; however, there was no correlation between serum prolidase levels and bone turnover markers in the postmenopausal osteoporotic group.…”

“…This recycling is important for collagen resynthesis and cell growth [10,11]. Prolidase enzyme activity has been investigated in the context of various disorders such as coronary artery disease [12], osteoporosis [4,7], osteoarthritis [10], uremic bone disease [13], and osteogenesis imperfecta [14]. These disorders have showed a relationship between serum prolidase concentrations and disease activity and/or bone metabolism.…”