Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells.
Biglycan (bgn) is an extracellular matrix proteoglycan that is enriched in bone and other skeletal connective tissues. Previously, we generated bgn-deficient mice and showed that they developed age-dependent osteopenia. To identify the cellular events that might contribute to this progressive osteoporosis, we measured the number of osteogenic precursors in the bone marrow of normal and mutant mice. The number of colonies, indicative of the colony-forming unit potential of fibroblasts (CFU-F), gradually decreased with age. By 24 weeks of age, colony formation in the bgn knockout (KO) mice was significantly more reduced than that in the wild type (wt) mice. This age-related reduction was consistent with the extensive osteopenia previously shown by X-ray analysis and histological examination of 24-week-old bgn KO mice. Because bgn has been shown previously to bind and regulate transforming growth factor beta (TGF-beta) activity, we also asked whether this growth factor would affect colony formation. TGF-beta treatment significantly increased the size of the wt colonies. In contrast, TGF-beta did not significantly influence the size of the bgn colonies. An increase in apoptosis in bgn-deficient bone marrow stromal cells (BMSCs) was observed also. The combination of decreased proliferation and increased apoptosis, if it occurred in vivo, would lead to a deficiency in the generation of mature osteoblasts and would be sufficient to account for the osteopenia developed in the bgn KO mice. The bgn KO mice also were defective in the synthesis of type I collagen messenger RNA (mRNA) and protein. This result supports the suggestion that the composition of the extracellular matrix may be regulated by specific matrix components including bgn.
Chen
Xiao-Dong
XD
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Shi
Songtao
S
Xu
Tianshun
T
Robey
Pamela Gehron
PG
Young
Marian F
MF
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D058578:Biglycan; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D024042:Collagen Type I / Q000378:metabolism; D003114:Colony-Forming Units Assay; D016326:Extracellular Matrix Proteins; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D010024:Osteoporosis / Q000473:pathology*; D011509:Proteoglycans / Q000172:deficiency* / Q000235:genetics; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C546885:Bgn protein, mouse; D058578:Biglycan; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta