Schneir M, Ramamurthy N, Golub L
Department of Basic Science, School of Dentistry, University of Southern California, Los Angeles 90089.
Matrix. 1990 May;10(2):112-23. doi: 10.1016/s0934-8832(11)80177-0.
Daily minocycline-treatment of streptozotocin-induced diabetic rats not only prevented a diabetes-caused atrophy of skin collagen mass (10-mos old rats), but also normalized skin collagen mass to match that of growing (ca. 1%/d) non-diabetic controls (4- and 5-mos old rats). The causative mechanism by which minocycline-treatment normalizes skin collagen mass must, in part, be related to a general anabolic effect on growth (body weight) because the effect on skin collagen mass correlates strongly to that on body weight. Consequently, a minocycline-stimulated increase of a systemic factor (such as insulin-like growth factor) is not unlikely. The anabolic effect of minocycline-treatment of diabetic rats is also expressed as a normalized cellular ribosome mass (an index of total protein synthetic capacity) and a normalized absolute rate of collagen production. (Calculation of an absolute rate was justified by an apparent maximum saturation of the prolyl-tRNA pool(s) of skin, maximum saturation obtained by the pool-flooding approach). The normalized skin ribosome amount does not, however, explain a selective effect of minocycline-treatment on collagen production as opposed to that for non-collagen protein, this selective effect measured as relative collagen production. To explain such selectivity, the inhibition of diabetes-induced excess skin collagenase activity seems unlikely. (This inference is based on results from a preliminary study indicating that recently [less than 2 h] synthesized collagen is not degraded by the excess collagenase in skin of diabetic rats). Thus, the principal collagen fraction acted on by pathologically excess collagenase might be collagen at a later stage (greater than 2 h after synthesis) in its life cycle. (Another possibility for the selective effect of minocycline on collagen production, as yet untested, is reduced intracellular procollagen degradation.) Overall, this is the first study aimed at discerning the mechanism(s) by which minocycline-treatment enhances the rate of collagen production in tissues of a diabetic rat. For future studies, the extent to which the positive effect on growth, ribosome mass, and rate of collagen production contributes to the change of collagen mass must, along with the known minocycline-inhibition of collagenase activity, be quantified. Such quantification is a prerequisite for evaluating the chemotherapeutic efficacy of minocycline-treatment on collagen-degradative diseases.
对链脲佐菌素诱导的糖尿病大鼠每日给予米诺环素治疗，不仅可预防糖尿病引起的皮肤胶原量萎缩（10月龄大鼠），还可使皮肤胶原量恢复正常，与生长中的（约每日1%）非糖尿病对照大鼠（4和5月龄大鼠）的胶原量相当。米诺环素治疗使皮肤胶原量恢复正常的致病机制，部分必定与对生长（体重）的一般合成代谢作用有关，因为对皮肤胶原量的影响与对体重的影响密切相关。因此，米诺环素刺激全身因子（如胰岛素样生长因子）增加并非不可能。米诺环素治疗糖尿病大鼠的合成代谢作用还表现为细胞核糖体质量正常化（总蛋白合成能力的指标）和胶原产生的绝对速率正常化。（通过皮肤脯氨酰-tRNA池的明显最大饱和度证明了绝对速率的计算合理，通过池灌注法获得最大饱和度）。然而，皮肤核糖体数量正常化并不能解释米诺环素治疗对胶原产生相对于非胶原蛋白质产生的选择性作用，这种选择性作用以相对胶原产生来衡量。为了解释这种选择性，抑制糖尿病诱导的皮肤胶原酶活性增加似乎不太可能。（这一推断基于一项初步研究的结果，该研究表明，最近[不到2小时]合成的胶原不会被糖尿病大鼠皮肤中的过量胶原酶降解）。因此，病理上过量胶原酶作用的主要胶原部分可能是其生命周期后期（合成后超过2小时）的胶原。（米诺环素对胶原产生选择性作用的另一种可能性，尚未得到检验，是细胞内前胶原降解减少）。总体而言，这是第一项旨在探究米诺环素治疗提高糖尿病大鼠组织中胶原产生速率机制的研究。对于未来的研究，对生长、核糖体质量和胶原产生速率的积极作用在多大程度上导致胶原量的变化，必须与已知的米诺环素对胶原酶活性的抑制作用一起进行量化。这种量化是评估米诺环素治疗对胶原降解性疾病化疗疗效的先决条件。
