Strontium ranelate reduces cartilage degeneration and subchondral bone remodeling in rat osteoarthritis model

Authors

De-gang Yu, Hui-feng Ding, Yuan-qing Mao, Ming Liu, Bo Yu, Xin Zhao,Xiao-qing Wang, Yang Li, Guang-wang Liu, Shao-bo Nie, Shen Liu andZhen-an Zhu

Abstract

Medial meniscal tear (MMT) operation was performed in adult SD rats to induce OA. SR (625 or 1800 mg·kg−1·d−1) was administered via gavage for 3 or 6 weeks. After the animals were sacrificed, articular cartilage degeneration was evaluated using toluidine blue O staining, SOX9 immunohistochemistry and TUNEL assay. The changes in microarchitecture indices and tissue mineral density (TMD), chemical composition (mineral-to-collagen ratio), and intrinsic mechanical properties of the subchondral bones were measured using micro-CT scanning, confocal Raman microspectroscopy and nanoindentation testing, respectively. The high-dose SR significantly attenuated cartilage matrix and chondrocyte loss at 6 weeks, and decreased chondrocyte apoptosis, improved the expression of SOX9, a critical transcription factor responsible for the expression of anabolic genes type II collagen and aggrecan, at both 3 and 6 weeks. Meanwhile, the high-dose SR also significantly attenuated the subchondral bone remodeling at both 3 and 6 weeks, as shown by the improved microarchitecture indices, TMD, mineral-to-collagen ratio and intrinsic mechanical properties. In contrast, the low-dose SR did not significantly change all the detection indices of cartilage and bone at both 3 and 6 weeks. The high-dose SR treatment can reduce articular cartilage degeneration and subchondral bone remodeling in the rat MMT model of OA.

Link to Article

http://dx.doi.org/10.1038/aps.2012.167

Indentation properties and glycosaminoglycan content of human menisci in the deep zone

Authors

John T. Moyer, Ryan Priest, Troy Bouman, Adam C. Abraham, Tammy L. Haut Donahue

Abstract

Menisci are two crescent shaped fibrocartilaginous structures that provide fundamental load distribution and support within the knee joint. Their unique shape transmits axial stresses (i.e. “body force”) into hoop or radial stresses. The menisci are primarily an inhomogeneous aggregate of glycosaminoglycans (GAGs) supporting bulk compression and type I collagen fibrils sustaining tension. It has been shown that the superficial meniscal layers are functionally homogeneous throughout the three distinct regions (anterior, central and posterior) using a 300 μm diameter spherical indenter tip, but the deep zone of the meniscus has yet to be mechanically characterized at this scale. Furthermore, the distribution and content of GAG throughout the human meniscal cross-section have not been examined. This study investigated the mechanical properties, via indentation, of the human deep zone meniscus among three regions of the lateral and medial menisci. The distribution of GAGs through the cross-section was also documented. Results for the deep zone of the meniscus showed the medial posterior region to have a significantly greater instantaneous elastic modulus than the central region. No significant differences in the equilibrium modulus were seen when comparing regions or the hemijoint. Histological results revealed that GAGs are not present until at least ∼600 μm from the meniscal surface. Understanding the role and distribution of GAG within the human meniscus in conjunction with the material properties of the meniscus will aid in the design of tissue engineered meniscal replacements.

Link to Article

http://dx.doi.org/10.1016/j.actbio.2012.12.033

Type I Phosphotidylinosotol 4-Phosphate 5-Kinase γ Regulates Osteoclasts in a Bifunctional Manner

Authors

Tingting Zhu, Jean C. Chappel, Fong-Fu Hsu, John Turk, Rajeev Aurora, Krzysztof Hyrc, Pietro De Camilli, Thomas J. Broekelmann, Robert P. Mecham, Steven L. Teitelbaum, and Wei Zou

Abstract

Type 1 phosphotidylinosotol-4 phosphate 5 kinase γ (PIP5KIγ) is central to generation of phosphotidylinosotol (4,5)P2 (PI(4,5)P2). PIP5KIγ also participates in cytoskeletal organization by delivering talin to integrins, thereby enhancing their ligand binding capacity. As the cytoskeleton is pivotal to osteoclast function, we hypothesized that absence of PIP5KIγ would compromise their resorptive capacity. Absence of the kinase diminishes PI(4,5) abundance and desensitizes precursors to RANK ligand-stimulated differentiation. Thus, PIP5KIγ−/− osteoclasts are reduced in number in vitro and confirm physiological relevance in vivo. Despite reduced numbers, PIP5KIγ−/− osteoclasts surprisingly have normal cytoskeletons and effectively resorb bone. PIP5KIγ overexpression, which increases PI(4,5)P2, also delays osteoclast differentiation and reduces cell number but in contrast to cells lacking the kinase, its excess disrupts the cytoskeleton. The cytoskeleton-disruptive effects of excess PIP5KIγ reflect its kinase activity and are independent of talin recognition. The combined arrested differentiation and disorganized cytoskeleton of PIP5KIγ-transduced osteoclasts compromises bone resorption. Thus, optimal PIP5KIγ and PI(4,5)P2 expression, by osteoclasts, are essential for skeletal homeostasis.

Link to Article

http://dx.doi.org/10.1074/jbc.M112.446054

Nano- to Macroscale Remodeling of Functional Tissue-Engineered Bone

Authors

Maria Ann Woodruff, Claudia Lange, Fulin Chen, Peter Fratzl, Dietmar Werner Hutmacher

Abstract

A higher degree of mineralization is found within scaffold groups implanted with cells compared to scaffold alone, demonstrating greater bone regenerative potential of cell-scaffold constructs Tissue engineered bone analysed using ESEM and SAXS demonstrates bone formation within the scaffold to be preferentially aligned around the scaffold struts. The mineral particles are not shown to orientate around the osteons within the native bone.

Link to Article

http://dx.doi.org/10.1002/adhm.201200289

Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation

Authors

Chang Yang, Jennifer L. Davis, Rong Zeng, Paras Vora, Xinming Su, Lynne I. Collins, Suwanna Vangveravong, Robert H. Mach, David Piwnica-Worms, Katherine N. Weilbaecher, Roberta Faccio, and Deborah Veis Novack

Abstract

Inhibitor of apoptosis (IAP) proteins play a central role in many types of cancer, and IAP antagonists are in development as anticancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-κB signaling through NF-κB–inducing kinase (NIK), which regulates osteoclasts. In bone metastasis, a positive feedback loop between tumors and osteoclasts promotes tumor growth and osteolysis. We therefore tested the effect of IAP antagonists on the bone microenvironment for metastasis. In both drug-sensitive and drug-resistant tumors, growth in bone was favored, as compared with other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Cotreatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist–enhanced tumor growth in bone and osteolysis. Thus, IAP antagonist–based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis, which may be prevented by antiresorptive agents. Significance: Although IAP antagonists are a class of anticancer agents with proven efficacy in multiple cancers, we show that these agents can paradoxically increase tumor growth and metastasis in the bone by stabilizing NIK and activating the alternative NF-κB pathway in osteoclasts. Future clinical trials of IAP antagonist–based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents.

Link to Article

http://dx.doi.org/10.1158/2159-8290.CD-12-0271

Effects of Non-Weight-Bearing on the Immature Femoral Head Following Ischemic Osteonecrosis: An Experimental Investigation in Immature Pigs

Authors

Harry K.W. Kim, Olumide Aruwajoye, Jeffrey Stetler, Alec Stall

Abstract

Local non-weight-bearing as a treatment for Legg-Calvé-Perthes disease remains controversial since a clear scientific basis for this treatment is lacking. The purpose of this study was to determine the effects of non-weight-bearing on decreasing the femoral head deformity following ischemic osteonecrosis and to investigate its biological effects. Unilateral femoral head ischemia was induced in sixteen piglets by placing a ligature around the femoral neck and transecting the ligamentum teres. Eight animals received a hind-limb amputation to prevent weight-bearing on the ischemic side (NWB group). The remaining eight piglets were allowed to bear weight as tolerated (WB group). The contralateral femoral heads of the WB group were used as normal controls. All animals were killed at eight weeks after induction of ischemia, when a deformity is expected in this model. Radiographic, microcomputed tomographic (micro-CT), and histomorphometric assessments were performed. Radiographic and micro-CT assessments showed significantly greater flattening of the infarcted epiphysis in the WB group compared with the NWB group. The mean epiphyseal quotient (ratio of femoral head height to diameter) was significantly lower in the WB group (0.29 ± 0.06) compared with the NWB group (0.41 ± 0.06, p < 0.001). Histomorphometric analyses showed that the mean percentage revascularization of the infarcted epiphysis was significantly greater in the NWB group (95% ± 14%) compared with the WB group (34% ± 33%, p < 0.0004), suggesting that revascularization was more rapid in the NWB group. Both histomorphometric and micro-CT analyses of trabecular bone parameters showed significantly decreased bone volume and decreased trabecular number in the infarcted epiphysis of the NWB group compared with the WB group (p < 0.05). Local non-weight-bearing decreased the deformity following ischemic femoral head osteonecrosis and increased the rates of revascularization and resorption of the infarcted epiphysis. Local non-weight-bearing was mechanically protective but biologically suboptimal following ischemic osteonecrosis since it increased the imbalance of bone resorption and formation.

Link to Article

http://dx.doi.org/10.2106/JBJS.L.00300