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Collagenase Cleavage of Type I Collagen Is Essential for Both Basal and Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor-Induced Osteoclast Activation and Has Differential Effects on Discrete Bone Compartments

Cell Biology and Orthopedics, Yale University (R.C., R.B.), New Haven, Connecticut 06520; and Endocrine Unit (A.M., M.C.K., L.M.C., E.S.) and Arthritis Unit (M.B., S.M.K.), Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. E. Schipani, Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts 02114. E-mail: schipani{at}helix.mgh.harvard.edu.

Expression of a constitutively active PTH/PTHrP receptor in cells of osteoblast lineage in vivo (CL2+) causes increases in trabecular bone volume and trabecular bone formation and, conversely, a decrease in the periosteal mineral apposition rate. Collagenase-3 (matrix metalloprotease-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-wk-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 rr mice. Osteoclast number was increased in CL2+/rr animals compared with either wild-type or CL2+ mice, suggesting that collagenase-dependent collagen cleavage affected osteoclast function rather than osteoclast number and/or differentiation. Interestingly, the periosteal mineral apposition rate was similar in CL2+/rr and CL2+ animals and was significantly lower than that in wild-type animals. 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 increased osteoblast function. Lastly, it supports the hypothesis that collagenases can be a downstream effector of PTH/PTHrP receptor action in trabecular bone, but not in periosteum.