No abstract

Tendon injuries at the epicondyle can occur in athletes and workers whose job functions involve repetitive, high force hand activities, but the early pathophysiologic changes of tendon are not well known. The purpose of this study was to evaluate early tendon structural changes, specifically the formation of microtears, caused by cyclical loading. The Flexor Digitorum Profundus (FDP) muscle of nine New Zealand White rabbits was stimulated to contract repetitively for 80 h of cumulative loading over 14 weeks. The contralateral limb served as a control. The tendon at the medial epicondyle insertion site was harvested, sectioned, and stained. Microtears were quantified, using image analysis software, in four regions of the tendon, two regions along the enthesis and two distal to the enthesis. The tear density (loaded: 1329 ? 546 tears/mm2; unloaded: 932 ? 474 tears/mm2) and mean tear size (loaded: 18.3 f 6.1 pm'; unloaded: 14.0 k 4.8 pm2) were significantly greater in the loaded limb (p < 0.0001) across all regions compared to the unloaded contralateral limb. These early microstructural changes in a repetitively loaded tendon may initiate a degenerative process that leads to tendinosis.

Tendon healing and integration of tendon grafts may be site or donor specific. To determine if differences exist in sensitivity to growth factors that have the potential to influence tendon repair, we compared the effects of recombinant human insulin-like growth factor-I on various types of tendon segments. The dose response effects on proteoglycan, collagen, noncollagen protein, and DNA synthesis were investigated in short-term explant cultures of intrasynovial intermediate and proximal segments of deep flexor tendons extrasynovial segments of deep flexor tendons, and Achilles tendons of rabbits. The four different types of tendon segments cultured in media without recombinant human insulin-like growth factor-I synthesized similar amounts of each of the matrix components. Intrasynovial proximal segments synthesized 15 times less DNA than other tendon segments. Recombinant human insulin-like growth factor-I stimulated matrix and DNA synthesis of all tendon segments in a dose-dependent manner in intervals from 10 to 1,000 ng/ml. The potency (LogED50) of the stimulation did not differ between the segments. The estimated maximal stimulation (E(max)) of proteoglycan synthesis by recombinant human insulin-like growth factor-I was higher, and of collagen and noncollagen protein synthesis was lower, in intrasynovial proximal segments as compared with that of the other types of segments. In contrast, the estimated maximal stimulation of DNA synthesis by recombinant human insulin-like growth factor-I was 6-fold higher than controls in all types of tendons. These findings demonstrate differences in mitotic capacity between anatomical regions of tendons during culture without recombinant human insulin-like growth factor-I and in matrix synthesis after stimulation with it.

Summary:Flexor tendons have an intrinsic ability for repair, with a capacity to metabolize matrix components and to proliferate. To identify factors with the potential of affecting those abilities, the effects of recombinant human insulinlike growth factor (rhIGF-I), insulin and fetal calf serum (FCS) on the synthesis of proteoglycan, collagen, and non-collagen protein and cell proliferation were investigated in short-term explant cultures of the deep flexor tendon of the rabbit. Matrix synthesis and cell proliferation were stimulated dose dependently by rhIGF-I at doses between 10 and 250 and at 10-100 ng/ml, respectively, by insulin at 250-5,000 ng/ml, and by FCS at 2-15%. Estimated maximal stimulation (Emax) of up to three times the control value was observed with rhIGF-I at 250 ng/ml. Maximal stimulation was observed at 5,000 n g h l with insulin, and FCS at 15%. rhIGF-I was more potent than insulin in stimulating protein synthesis and cell proliferation. The Emax of stimulation of proteoglycan and collagen synthesis by rhIGF-I were two times that of FCS, and the Em,, of cell proliferation by FCS was twice that of rhIGF-I. Growth factors thus have the ability to stimulate matrix synthesis and cell proliferation in rabbit flexor tendon. This provides a rationale for further studies on the role of growth factors in flexor tendon healing in humans.

To improve the understanding of factors with the potential of affecting the healing of flexor tendons, this study compared the cellular effects of recombinant human insulin-like growth factor-II with those of recombinant human insulin-like growth factor-I in matched pairs of deep flexor tendons of young rabbits. Dose-response effects on the synthesis of DNA and matrix proteins of either factor alone or in combination were investigated in short-term culture, and effects on synthesis and turnover of matrix components were compared in long-term culture. Both factors stimulated proteoglycan, collagen, noncollagen protein, and DNA synthesis in a dose-dependent manner in the range of 10-500 ng/ml. Insulin-like growth factor-I increased proteoglycan synthesis to as much as six times that of controls but was less potent than insulin-like growth factor-II. Both factors stimulated increased cell proliferation by as much as five times compared with control values, but insulin-like growth factor-I was more potent than insulin-like growth factor-II. The two factors in combination did not enhance the synthesis of matrix proteins and DNA as compared with either factor alone. Insulin-like growth factor-I counteracted the decrease in collagen synthesis and stimulated protein synthesis to a higher degree than insulin-like growth factor-II in long-term culture. Both factors had similar effects on matrix turnover, with estimated half times (t1/2) for elimination of newly labeled proteoglycans and proteins of 11 and 8 days, respectively. Insulin-like growth factor-II is capable of stimulating cell proliferation and matrix metabolism in tendon explants of young rabbits at levels similar to those of insulin-like growth factor-I; in combination, the two growth factors are unable to augment the stimulatory effects of either of the factors alone.