Deficiency in Perlecan/HSPG2 During Bone Development Enhances Osteogenesis and Decreases Quality of Adult Bone in Mice

Abstract

Perlecan/Hspg2 (Pln) is a large heparan sulfate proteoglycan abundant in the extracellular matrix of cartilage and the lacuno-canalicular space of adult bones. While Pln function during cartilage development is critical, evidenced by deficiency disorders including Schwartz-Jampel Syndrome and dyssegmental dysplasia Silverman-Handmaker type, little is known about its function in development of bone shape and quality. The purpose of this study was to understand the contribution of Pln to bone geometric and mechanical properties. We used hypomorph mutant mice that secrete negligible amount of Pln into skeletal tissues and analyzed their adult bone properties using micro-computed tomography and three-point-bending tests. Bone shortening and widening in Pln mutants was observed and could be attributed to loss of growth plate organization and accelerated osteogenesis that was reflected by elevated cortical thickness at older ages. This effect was more pronounced in Pln mutant females indicating a gender-specific effect of Pln deficiency on bone geometry. Additionally, mutant females, and to a lesser extent mutant males, increased their elastic modulus and bone mineral densities to counteract changes in bone shape, but at the expense of increased brittleness. In summary, Pln deficiency alters cartilage matrix patterning and, as we now show, coordinately influences bone formation and calcification.

Knockdown of the pericellular matrix molecule perlecan lowers in situ cell and matrix stiffness in developing cartilage

“…1). Homozygous animals showed low levels of perlecan that appeared to be restricted to the intracellular compartment, which is consistent with a previous report that showed that perlecan in (Neo/Neo) mice is sequestered in the endoplasmic reticulum and is likely degraded (Lowe et al, 2014). In heterozygous and wild-type E16.5 embryos, perlecan was found throughout the distal humerus, (Fig.…”

Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation <i>in vitro </i>

“…A report concluded that there are 15 members in the HSPGs. Among these members, Sdc2 and HSPG2 have been suggested to be involved in skeleton formation (41,42).…”

“…Sdc2 is abundant in putative precursor cells of hard and connective tissue, and its expression is high in prechondrogenic cells, decreases in differentiating chondrocytes, and persists in the perichondrium and periosteum at the onset of osteogenesis (42). HSPG2 is abundant in the extracellular matrix of cartilage and the lacunocanalicular space of adult bones, and deficiency in HSPG2 during bone development enhances osteogenesis and decreases quality of adult bone in mice (41).…”

“…Given HSPGs are receptors for apoE, Sdc2 and HSPG2 have been suggested to be involved in skeleton formation (41,42), and thus we analyzed the regulation of Sdc2 and HSPG2 by E2 during osteoblast differentiation as well. Our results showed that either in the saline group or in E2 treated group, both Sdc2 and HSPG2 genes were induced at day 5 and 25 of differentiation ( Figures 6A and 6D, p < 0.05, p < 0.01, p < 0.001).…”

The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy

“…In addition to the disorganization of the growth plate and chondro-osseous junction of bones caused by the absence of perlecan, there are other distortions in the growth of joints including the temporo-mandibular joint, myotonia and electrical disturbances of muscle and modifications to the structures of facial bones (30). Moreover, perlecan deficiency in hypomorphic mutant mice influences bone formation by enhancing osteogenesis and concurrently affects mineralization, leading to increased brittleness at older ages (31). …”