Abstract
In studies intended to improve healing of transected Achilles tendon, effective was a stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419). Currently in clinical trials for inflammatory bowel disease (PLD-116, PL 14736, Pliva), it ameliorates internal and external wound healing. In rats, the right Achilles tendon transected (5 mm proximal to its calcaneal insertion) presents with a large tendon defect between cut ends. Agents (/kg b.w., i.p., once time daily) (BPC 157 (dissolved in saline, with no carrier addition) (10 μg, 10 ng or 10 pg) or saline (5.0 ml)), were firstly applied at 30 min after surgery, the last application at 24 h before autopsy. Achilles functional index (AFI) was assessed once time daily. Biomechanical, microscopical and macroscopical assessment was on day 1, 4, 7, 10 and 14. Controls generally have severely compromised healing. In comparison, pentadecapeptide BPC 157 fully improves recovery: (i) biomechanically, increased load of failure, load of failure per area and Young’s modulus of elasticity; (ii) functionally, significantly higher AFI-values; (iii) microscopically, more mononuclears and less granulocytes, superior formation of fibroblasts, reticulin and collagen; (iv) macroscopically, smaller size and depth of tendon defect, and subsequently the reestablishment of full tendon integrity. Likewise, unlike TGF-β, pentadecapeptide BPC 157, presenting with no effect on the growth of cultured cell of its own, consistently opposed 4-hydroxynonenal (HNE), a negative modulator of the growth. HNE-effect is opposed in both combinations: BPC 157 + HNE (HNE growth inhibiting effect reversed into growth stimulation of cultured tendocytes) and HNE + BPC 157(abolished inhibiting activity of the aldehyde), both in the presence of serum and serum deprived conditions. In conclusion, these findings, particularly, Achilles tendon transection fully recovered in rats, peptide stability suitable delivery, usefully favor gastric pentadecapeptide BPC 157 in future Achilles tendon therapy.
Introduction
Most protein growth factors that might improve the healing following tendon rupture are rapidly metabolized by the organism [1]. To benefit from an otherwise weak activity of peptides, parallel with attempts to further improvement of the peptides carriers [25] needed for peptidergic agents activity, an injection close to the site of the wound (urogastrone (epidermal growth factor (EGF)) [7], or into the wound (the recombinant LR3-IGF-I variant form of IGF-I) [10] or collagen sponges in the tendon defects (growth and differentiation factors (GDFs) 5,6,7) [1] were suggested. However, all special regimens reflect uncertain and limited delivery regularly inappropriate for routine use. To this end, our focus is a stable gastric pentadecapeptide BPC 157, currently in clinical trials for inflammatory bowel disease (PL-10, PLD-116, PL 14736, Pliva).
Transected rat Achilles tendon likely recovery begins with pentadecapeptide BPC 157 active given systemically and/or locally [8], [12], [16], [17], [19], [20], [21], [31], and its healing effects on various tissues [8], [12], [16], [17], [19], [20], [21], [31]. Initially, as a gastric pentadecapeptide, BPC 157 opposes a variety of gastrointestinal lesions (i.e., [12], [19]). Later, it aids in healing of different wounds (i.e., skin [17], corneal [8], colon–colon anastomosis [31], deep skin burn [12], segmental osteoperiosteal bone defects [16]). Also, it has an angiogenic effect [21] and modulates NO-synthesis [19]. This may directly affect repair of connective tissues [6], as an ordered multistage process involving inflammation and oxidative stress. Since oxidative stress with consequent lipid peroxidation and production of HNE has an important role in pathophysiology of tissue damage, inflammation and cell growth regulation [29], [30], we investigate the influence of BPC 157 on the growth of cultured tendocytes obtained from the rat Achilles tendon, quiescent or treated in vitro with HNE. A comparison to transforming growth factor beta (TGF-β) a factor known to increase matrix expression [14] was done.
Besides, this gastric pentadecapeptide BPC 157 likely controls functions of collagen fragments [12], [23]. Likewise, it has special relation over bone morphogenetic proteins [12], [23]. High stability [8], [12], [16], [17], [19], [20], [21], [28] (i.e., no degradation in human gastric juice even for 24 h, unlike rapidly degraded h-TGF, and h-EGF) [26]) permits no carrier used in previous [8], [12], [16], [17], [19], [20], [21], [28] and present studies. Together, this means that unlike limited delivery of other peptides [1], [7], [9], [23] this stable pentadecapeptide is highly resistant to otherwise inescapable degradation of peptides. Likewise, acting alone, without carrier, it presents a healing potential of its own [8], [12], [16], [17], [19], [20], [21], [31], and may be suitable for therapy of complex structures such as the Achilles tendon.
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Section snippets
Drugs
Pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419) (manufactured by Diagen, d.o.o., Ljubljana, Slovenia) is a partial of sequence of human gastric juice protein BPC, freely soluble in water at pH 7.0 and in saline. It was prepared as described before [8], [12], [16], [17], [19], [20], [21], [31]. Peptide with 99% (HPLC) purity (1-des-Gly peptide as impurity), dissolved in saline was used in all of the experiments [8], [12], [16], [17], [19], [20], [21], [31]. TGF-β1 was obtained from Sigma,
Evaluation of deficit and recovery of Achilles tendon following transection
Impaired healing of transected right Achilles tendon in controls follows the course and the figures commonly reported by others (i.e., [2]). Large tendon defect appeared between the cut ends of Achilles tendon, measuring (median [minimum–maximum]) 7.6 mm [6.2–8.3] immediately after transection and 7.4 mm [6.2–7.9] on day 1.
Noteworthy, positive outcome in pentadecapeptide BPC 157 rats (μg- or ng-regimen) is supported by functional, biomechanical, microscopical and macroscopical findings (Table 1
Discussion
Stable peptide can play a major role in generating therapy for tendon healing and this study focus was on a stable gastric pentadecapeptide BPC 157. Currently in clinical trials for inflammatory bowel disease (PLD-116, PL-14736, Pliva), it ameliorates internal and external wound healing [8], [12], [16], [17], [19], [20], [21], [31]. Here, systemic administration-improvement of an injured tendon follows from a general evidence presenting this tendon repair similar to the repair of other
Acknowledgements
This study is sponsored by Ministry of Science Republic of Croatia.View full text
Copyright © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.