Expression of a constitutively active PTH/PTHrP receptor in cells of osteoblast lineage in vivo (CL2+) causes an increase in trabecular bone volume and trabecular bone formation, and, conversely, a decrease in periosteal mineral apposition rate. Collagenase-3 (MMP-13) is a downstream target of PTH action. To investigate the relevance of collagenase cleavage of type I collagen for the CL2+ bone phenotype, we bred CL2+ animals with mice carrying a mutated col11 gene that encodes a protein resistant to digestion by collagenase-3 and other collagenases (rr). Adult tibias and parietal bones from 4-week old double mutant animals (CL2+/rr) and from control littermates were analyzed. Trabecular bone volume was higher in CL2+/rr than in CL2+ mice. This increase occurred despite a modest reduction in bone formation rate, which was, however, still significantly higher that in wild-type littermates, and therefore must reflect decreased bone resorption in the rr mice. Osteoclast number was increased in CL2+/rr animals in comparison to either wild-type or CL2+ mice, suggesting that collagenase-dependent collagen cleavage affected osteoclast function rather than osteoclast number and/or differentiation. Interestingly, periosteal mineral apposition rate was similar in both CL2+/rr and CL2+ animals, and significantly lower than in wild-type. Our study provides evidence that collagenase activity is important for both basal and PTH/PTHrP receptor-dependent osteoclast activation; furthermore, it indicates that a mild impairment of osteoclast activity is still compatible with an increased osteoblast function; lastly, it supports the hypothesis that collagenases can be a downstream effector of the PTH/PTHrP receptor action in the trabecular bone but not in the periosteum.