title: Perlecan-containing pericellular matrix regulates solute transport and mechanosensing within the osteocyte lacunar-canalicular system.
abstract: The pericellular matrix (PCM), a thin coating surrounding nearly all mammalian cells, plays a critical role in many cell-surface phenomena. In osteocytes, the PCM is believed to control both "outside-in" (mechanosensing) and "inside-out" (signaling molecule transport) processes. However, the osteocytic PCM is challenging to study in situ because it is thin (∼100 nm) and enclosed in mineralized matrix. To this end, we recently developed a novel tracer velocimetry approach that combined fluorescence recovery after photobleaching (FRAP) imaging with hydrodynamic modeling to quantify the osteocytic PCM in young murine bone. In this study, we applied the technique to older mice expressing or deficient for perlecan/HSPG2, a large heparan-sulfate proteoglycan normally secreted in osteocytic PCM. The objectives were (1) to characterize transport within an altered PCM; (2) to test the sensitivity of our approach in detecting the PCM alterations; and (3) to dissect the roles of the PCM in osteocyte mechanosensing. We found that: (1) solute transport increases in the perlecan-deficient (hypomorphic [Hypo]) mice compared with control mice; (2) PCM fiber density decreases with aging and perlecan deficiency; (3) osteocytes in the Hypo bones are predicted to experience higher shear stress (+34%), but decreased fluid drag force (-35%) under 3-N peak tibial loading; and (4) when subjected to tibial loading in a preliminary in vivo experiment, the Hypo mice did not respond to the anabolic stimuli as the CTL mice did. These findings support the hypothesis that the PCM fibers act as osteocyte's sensing antennae, regulating load-induced cellular stimulations and thus bone's sensitivity and in vivo bone adaptation. If this hypothesis is further confirmed, osteocytic PCM could be new targets to develop osteoporosis treatments by modulating bone's intrinsic sensitivity to mechanical loading and be used to design patient-specific exercise regimens to promote bone formation.
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, DE, USA; Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College, Chongqing University, Chongqing, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Lai
authors.forename: Christopher
authors.initials: C
authors.lastname: Price
authors.forename: William R
authors.initials: WR
authors.lastname: Thompson
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Tonima R
authors.initials: TR
authors.lastname: Quabili
authors.forename: Wei-Ju
authors.initials: WJ
authors.lastname: Tseng
authors.forename: Xiaowei Sherry
authors.initials: XS
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Pan
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Kirn-Safran
authors.forename: Mary C
authors.initials: MC
authors.lastname: Farach-Carson
authors.forename: Liyun
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D051379:Mice; D010011:Osteocytes / Q000378:metabolism*
chemical_list: D019812:Heparan Sulfate Proteoglycans; C071927:perlecan
keywords: FLUID DRAG FORCE; HSPG2; MECHANOSENSING; PERICELLULAR MATRIX; PERLECAN DEFICIENCY