The process of
bone resorption by osteoclasts involves the dissolution of
mineral salts and enzymatic degradation of the mainly collagenous extracellular matrix.
Cysteine proteinases, which can efficiently degrade
collagen at acidic pH, have been suggested to play an important role in the bone resorptive process. The
cysteine proteinase cathepsin L is secreted by osteoclasts, and inhibitors of this
enzyme can prevent
bone resorption in vitro. The activity of acetyl-
leu-leu-norleucinol (ALLN), a selective inhibitor of
cathepsin L, was investigated in two models of
bone resorption in vivo. In the first study, the ability of ALLN to inhibit
bone resorption was investigated in Ro-13-6298 (arotinoid)-treated thyroparathyroidectomized (TPTX) rats. ALLN [100 mg/kg, intraperitoneally (i.p.)] inhibited
hypercalcemia by 62.8% acutely (p < 0.001), compared to 94.9% (p < 0.001) inhibition by
salmon calcitonin (sCT) (10 IU/kg, subcutaneously). In rats treated for 3 days with ALLN, arotinoid-induced reduction in cortical bone
mineral density measured by peripheral quantitative computed tomography (pQCT) was inhibited by 86.4% (p < 0.05) in rats treated with ALLN 100 mg/kg, i.p., and by 82% in rats treated with 50 mg/kg, i.p. (p < 0.05). In a second study, the efficacy of ALLN was tested in a longitudinal study in ovariectomized (ovx) rats. Bone loss, measured by pQCT, was unaffected by treatment with ALLN. The
bisphosphonate alendronate, however, inhibited bone loss in this model. These data demonstrate the ability of a
cathepsin L inhibitor to inhibit
bone resorption in arotinoid-treated TPTX rats, a process which may be dependent on the activity of
cathepsin L-like
cysteine proteinases. In contrast to its effects in TPTX rats, ALLN had no inhibitory activity on
bone resorption in ovx rats. It is possible that in chronic
bone resorption in ovx rats, the activity of other
enzymes such as
cathepsins OC-2 or K allows the process of resorption to continue even when
cathepsin L is inhibited by ALLN. Further studies are required to determine why the activity of ALLN varies between different animal models. These data indicate that there may be variations in the effects of drugs in different animal models of
bone resorption which should be considered when investigating novel antiresorptive
therapies.