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Pal S.,Stanford University | Besier T.F.,University of Auckland | Draper C.E.,Stanford University | Fredericson M.,Stanford University | And 4 more authors.
Journal of Orthopaedic Research | Year: 2012

Patellofemoral (PF) pain is a common ailment of the lower extremity. A theorized cause for pain is patellar maltracking due to vasti muscle activation imbalance, represented as large vastus lateralis:vastus medialis (VL:VM) activation ratios. However, evidence relating vasti muscle activation imbalance to patellar maltracking is limited. The purpose of this study was to investigate the relationship between VL:VM activation ratio and patellar tracking measures, patellar tilt and bisect offset, in PF pain subjects and pain-free controls. We evaluated VL:VM activation ratio and VM activation delay relative to VL activation in 39 PF pain subjects and 15 pain-free controls during walking. We classified the PF pain subjects into normal tracking and maltracking groups based on patellar tilt and bisect offset measured from weight-bearing magnetic resonance imaging. Patellar tilt correlated with VL:VM activation ratio only in PF pain subjects classified as maltrackers. This suggests that a clinical intervention targeting vasti muscle activation imbalance may be effective only in PF pain subjects classified as maltrackers. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. Source


Wang L.,Physical Medicine and Rehabilitation Service | Wang L.,Stanford University | Shi X.,Physical Medicine and Rehabilitation Service | Shi X.,Stanford University | And 10 more authors.
Bone | Year: 2010

Previously we observed that capsaicin treatment in rats inhibited sensory neuropeptide signaling, with a concurrent reduction in trabecular bone formation and bone volume, and an increase in osteoclast numbers and bone resorption. Calcitonin-gene-related peptide (CGRP) is a neuropeptide richly distributed in sensory neurons innervating the skeleton and we postulated that CGRP signaling regulates bone integrity. In this study we examined CGRP effects on stromal and bone cell differentiation and activity in vitro. CGRP receptors were detected by immunocytochemical staining and real time PCR assays in mouse bone marrow stromal cells (BMSCs) and bone marrow macrophages (BMMs). CGRP effects on BMSC proliferation and osteoblastic differentiation were studied using BrdU incorporation, PCR products, alkaline phosphatase (ALP) activity, and mineralization assays. CGRP effects on BMM osteoclastic differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase positive (TRAP+) multinucleated cells, pit erosion area, mRNA levels of TRAP and cathepsin K, and nuclear factor-κB (NF-κB) nuclear localization. BMSCs, osteoblasts, BMMs, and osteoclasts all expressed CGRP receptors. CGRP (10κ10-10κ8 M) stimulated BMSC proliferation, up-regulated the expression of osteoblastic genes, and increased ALP activity and mineralization in the BMSCs. In BMM cultures CGRP (10κ8 M) inhibited receptor activator of NF-κB ligand (RANKL) activation of NF-κB. CGRP also down-regulated osteoclastic genes like TRAP and cathepsin K, decreased the numbers of TRAP+ cells, and inhibited bone resorption activity in RANKL stimulated BMMs. These results suggest that CGRP signaling maintains bone mass both by directly stimulating stromal cell osteoblastic differentiation and by inhibiting RANKL induced NF-κB activation, osteoclastogenesis, and bone resorption. © 2009 Elsevier Inc. Source


Temiyasathit S.,Bone and Joint Rehabilitation R and nter | Temiyasathit S.,Stanford University | Tang W.J.,Bone and Joint Rehabilitation R and nter | Leucht P.,Stanford University | And 9 more authors.
PLoS ONE | Year: 2012

Primary cilia, solitary microtubule-based structures that grow from the centriole and extend into the extracellular space, have increasingly been implicated as sensors of a variety of biochemical and biophysical signals. Mutations in primary cilium-related genes have been linked to a number of rare developmental disorders as well as dysregulation of cell proliferation. We propose that primary cilia are also important in mechanically regulated bone formation in adults and that their malfunction could play a role in complex multi-factorial bone diseases, such as osteoporosis. In this study, we generated mice with an osteoblast- and osteocyte-specific knockout of Kif3a, a subunit of the kinesin II intraflagellar transport (IFT) protein; IFT is required for primary cilia formation, maintenance, and function. These Colα1(I) 2.3-Cre;Kif3a fl/fl mice exhibited no obvious morphological skeletal abnormalities. Skeletally mature Colα1(I) 2.3-Cre;Kif3a fl/fl and control mice were exposed to 3 consecutive days of cyclic axial ulna loading, which resulted in a significant increase in bone formation in both the conditional knockouts and controls. However, Colα1(I) 2.3-Cre;Kif3a fl/fl mice did exhibit decreased formation of new bone in response to mechanical ulnar loading compared to control mice. These results suggest that primary cilia act as cellular mechanosensors in bone and that their function may be critical for the regulation of bone physiology due to mechanical loading in adults. Source


Kwon R.Y.,Bone and Joint Rehabilitation R and nter | Kwon R.Y.,Stanford University | Temiyasathit S.,Bone and Joint Rehabilitation R and nter | Temiyasathit S.,Stanford University | And 5 more authors.
FASEB Journal | Year: 2010

Primary cilia are chemosensing and mechanosensing organelles that regulate remarkably diverse processes in a variety of cells. We previously showed that primary cilia play a role in mediating mechanosensing in bone cells through an unknown mechanism that does not involve extracellular Ca2+-dependent intracellular Ca2+ release, which has been implicated in all other cells that transduce mechanical signals via the cilium. Here, we identify a molecular mechanism linking primary cilia and bone cell mechanotransduction that involves adenylyl cyclase 6 (AC6) and cAMP. Intracellular cAMP was quantified in MLO-Y4 cells exposed to dynamic flow, and AC6 and primary cilia were inhibited using RNA interference. When exposed to flow, cells rapidly (<2 min) and transiently decreased cAMP production in a primary ciliumdependent manner. RT-PCR revealed differential expression of the membrane-bound isoforms of adenylyl cyclase, while immunostaining revealed one, AC6, preferentially localized to the cilium. Further studies showed that decreases in cAMP in response to flow were dependent on AC6 and Gd3+-sensitive channels but not intracellular Ca2+ release and that this response mediated flow-induced COX-2 gene expression. The signaling events identified provide important details of a novel early mechanosensing mechanism in bone and advances our understanding of how signal transduction occurs at the primary cilium. © FASEB. Source

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