Phenotypic Effects of Biglycan Deficiency Are Linked to Collagen Fibril Abnormalities, Are Synergized by Decorin Deficiency, and Mimic Ehlers-Danlos-Like Changes in Bone and Other Connective Tissues

Abstract

Decorin (dcn) and biglycan (bgn), two members of the family of small leucine-rich proteoglycans (SLRPs), are the predominant proteoglycans expressed in skin and bone, respectively. Targeted disruption of the dcn gene results in skin laxity and fragility, whereas disruption of the bgn gene results in reduced skeletal growth and bone mass leading to generalized osteopenia, particularly in older animals. Here, we report that bgn deficiency leads to structural abnormality in collagen fibrils in bone, dermis, and tendon, and to a "subclinical" cutaneous phenotype with thinning of the dermis but without overt skin fragility. A comparative ultrastructural study of different tissues from bgn-and dcn-deficient mice revealed that bgn and dcn deficiency have similar effects on collagen fibril structure in the dermis but not in bone. Ultrastructural and phenotypic analysis of newly generated bgn/dcn double-knockout (KO) mice revealed that the effects of dcn and bgn deficiency are additive in the dermis and synergistic in bone. Severe skin fragility and marked osteopenia characterize the phenotype of double-KO animals in which progeroid changes are observed also in the skin.

Impaired posterior frontal sutural fusion in the biglycan/decorin double deficient mice

“…In addition, the BMP2/ 4 regulation of the osteoblast differentiation markers, Runx-2, Osterix, and Alkaline phosphatase, appears to be dependent on Dlx-5 (17,19,20). Impaired PFS fusion in the Bgn/Dcn double deficient mice may be due to failure of appropriate expression of signaling molecules involved in promoting bone formation and mineralization, which is consistent with previous findings of severe osteopenia (2,5) and decreased expression of Dlx-5 in the cranial sutures. However, as has been suggested by others, it is important to consider the possibility that additional factors besides increased or decreased bone formation could control abnormal cranial suture fusion (3,6).…”

“…All mice were genotyped for Bgn and Dcn alleles by PCR analysis as described (5). PCR products were resolved by electrophoresis through 1.8% agarose gels, yielding bands of 212 bp for the Wt Bgn allele, 310 bp for the disrupted Bgn allele, 161 bp for the Wt Dcn allele, and 238 bp for the disrupted Dcn allele.…”

“…Because of their similarity in structure and their overlapping expression in skeletal and connective tissues, it is probable that Bgn and Dcn function redundantly. Support of this concept comes from the analysis of Bgn/Dcn double deficient mice that have a more severe phenotype in both long bone and skin (2,5) compared to Wt or singly deficient SLRP mice.…”

Tissue-specific Changes in the Hydroxylysine Content and Cross-links of Collagens and Alterations in Fibril Morphology in Lysyl Hydroxylase 1 Knock-out Mice

“…Abnormal collagen fibrils have similarly been found in mouse models with a deficiency in the small leucine-rich proteoglycans biglycan (39), decorin (40), fibromodulin (41), and lumican (42) that show EDS-like symptoms. These small leucinerich proteoglycans are extracellular matrix proteins that bind to TGF␤s, collagens, and other extracellular matrix proteins and have been shown to regulate collagen fibrillogenesis in vitro (43).…”

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

“…For instance, extracellular matrix proteoglycans, such as decorin (DCN), biglycan (BGN), and fibromodulin (FMOD), sequester TGF-␤ to limit its activity (34). Mice lacking DCN, BGN, or FMOD display elevated TGF-␤ activity and phenotypes observed in Marfan syndrome or Ehlers-Danlos syndrome (35)(36)(37). Indeed, proteoglycan deficiencies have been demonstrated in patients with these syndromes (38).…”