title: 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.
abstract: 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 col1 alpha 1 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.
authors.affiliation: Cell Biology and Orthopedics, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chiusaroli
authors.forename: A
authors.initials: A
authors.lastname: Maier
authors.forename: M C
authors.initials: MC
authors.lastname: Knight
authors.forename: M
authors.initials: M
authors.lastname: Byrne
authors.forename: L M
authors.initials: LM
authors.lastname: Calvi
authors.forename: R
authors.initials: R
authors.lastname: Baron
authors.forename: S M
authors.initials: SM
authors.lastname: Krane
authors.forename: E
authors.initials: E
authors.lastname: Schipani
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D017364:Collagenases / Q000378:metabolism*; D005260:Female; D008297:Male; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism*; D010521:Periosteum / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism*; D012886:Skull / Q000166:cytology / Q000378:metabolism*; D013977:Tibia / Q000166:cytology / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse