Abstract
Osteocytes project long, slender processes throughout the mineralized matrix of bone, where they connect and communicate with effector cells. The interconnected cellular projections form the functional lacunocanalicular system, allowing fluid to pass for cell-to-cell communication and nutrient and waste exchange. Prevention of mineralization in the pericellular space of the lacunocanalicular pericellular space is crucial for uninhibited interstitial fluid movement. Factors contributing to the ability of the pericellular space of the lacunocanalicular system to remain open and unmineralized are unclear. Immunofluorescence and immunogold localization by transmission electron microscopy demonstrated perlecan/Hspg2 signal localized to the osteocyte lacunocanalicular system of cortical bone, and this proteoglycan was found in the pericellular space of the lacunocanalicular system. In this study we examined osteocyte lacunocanalicular morphology in mice deficient in the large heparan sulfate proteoglycan perlecan/Hspg2 in this tissue. Ultrastructural measurements with electron microscopy of perlecan/Hspg2-deficient mice demonstrated diminished osteocyte canalicular pericellular area, resulting from a reduction in the total canalicular area. Additionally, perlecan/Hspg2-deficient mice showed decreased canalicular density and a reduced number of transverse tethering elements per canaliculus. These data indicated that perlecan/Hspg2 contributed to the integrity of the osteocyte lacunocanalicular system by maintaining the size of the pericellular space, an essential task to promote uninhibited interstitial fluid movement in this mechanosensitive environment. This work thus identified a new barrier function for perlecan/Hspg2 in murine cortical bone. © 2011 American Society for Bone and Mineral Research.
Highlights
Bone is a unique mineralized connective tissue that adapts its structure dynamically in response to its environment.[1]
Proteoglycans represent a major component of the pericellular material surrounding osteocyte processes[10] and are thought to comprise the transverse tethering elements in the lacunocanalicular system (LCS).[8]. The only heparan sulfate proteoglycan with sufficient size to span the pericellular space of the LCS is perlecan/Hspg2 (PLN).(11,12) The name perlecan means ‘‘string of pearls,’’ given because of its appearance as globules separated by rods when imaged by transmission electron microscopy (TEM) and atomic-force microscopy (AFM).(12,13) PLN is a very large five-domain heparan sulfate proteoglycan with a core protein of over 4000 amino acids.[14,15] The N-terminal domain I contains three GAG attachment sites, whereas the C-terminal domain V contains another variably used putative GAG attachment site.[16]
A compilation of studies indicates the approximate size of PLN to be 100 to 200 nm, making it the only heparan sulfate proteoglycan of which we are aware that could span the very large pericellular space of the osteocyte LCS
Summary
Bone is a unique mineralized connective tissue that adapts its structure dynamically in response to its environment.[1]. The mechanism of action behind this process is widely debated; You and colleagues proposed a strain amplification model to account for the ability of load-induced fluid shear stress to mechanically deform the osteocyte cell membrane on the order necessary to initiate a mechanosensitive response from osteocytes.[7] In this model, an uncharacterized organic matrix filled the pericellular space around the osteocyte processes. Proteoglycans represent a major component of the pericellular material surrounding osteocyte processes[10] and are thought to comprise the transverse tethering elements in the LCS.[8] The only heparan sulfate proteoglycan with sufficient size to span the pericellular space of the LCS is perlecan/Hspg (PLN).(11,12) The name perlecan means ‘‘string of pearls,’’ given because of its appearance as globules separated by rods when imaged by TEM and atomic-force microscopy (AFM).(12,13) PLN is a very large five-domain heparan sulfate proteoglycan with a core protein of over 4000 amino acids.[14,15] The N-terminal domain I contains three GAG attachment sites, whereas the C-terminal domain V contains another variably used putative GAG attachment site.[16]. PLN is abundantly secreted into the pericellular space of numerous tissues, near tissue barriers, and is ideally positioned to mediate signaling events by sequestering growth factors and binding integrins.[12,17,18,19,20,21,22] PLN and its long heparan sulfate chains regulate various physiologic functions in a variety of tissues where barriers are required, including separating epithelia and stroma, preventing cancer cell invasion,(23,24) maintaining the blood-brain barrier,(25) and controlling glomerular filtration and fluid movement.[26,27,28,29] heparan sulfate inhibits hydroxyapatite (HAP) formation.[30,31]
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