Exosomal transfer of osteoclast-derived miRNAs to chondrocytes contributes to osteoarthritis progression

AUTHORS

Jin Liu, Xiaohao Wu, Jun Lu, Guangxin Huang, Lei Dang, Huarui Zhang, Chuanxin Zhong, Zongkang Zhang, Dijie Li, Fangfei Li, Chao Liang, Yuanyuan Yu, Bao-Ting Zhang, Lin Chen, Aiping Lu & Ge Zhang

ABSTRACT

Osteoarthritis (OA) is a prevalent aging-related joint disease lacking disease-modifying therapies. Here, we identified an upregulation of circulating exosomal osteoclast (OC)-derived microRNAs (OC-miRNAs) during the progression of surgery-induced OA in mice. We found that reducing OC-miRNAs by Cre-mediated excision of the key miRNA-processing enzyme Dicer or blocking the secretion of OC-originated exosomes by short interfering RNA-mediated silencing of Rab27a substantially delayed the progression of surgery-induced OA in mice. Mechanistically, the exosomal transfer of OC-miRNAs to chondrocytes reduced the resistance of cartilage to matrix degeneration, osteochondral angiogenesis and sensory innervation during OA progression by suppressing tissue inhibitor of metalloproteinase-2 (TIMP-2) and TIMP-3. Furthermore, systemic administration of a new OC-targeted exosome inhibitor (OCExoInhib) blunted the progression of surgery-induced OA in mice. We suggest that targeting the exosomal transfer of OC-miRNAs to chondrocytes represents a potential therapeutic avenue to tackle OA progression.

Peptidomimetic inhibitor of L-plastin reduces osteoclastic bone resorption in aging female mice

AUTHORS

Hanan Aljohani, Joseph P. Stains, Sunipa Majumdar, Deepa Srinivasan, Linda Senbanjo & Meenakshi A. Chellaiah

ABSTRACT

L-plastin (LPL) was identified as a potential regulator of the actin-bundling process involved in forming nascent sealing zones (NSZs), which are precursor zones for mature sealing zones. TAT-fused cell-penetrating small molecular weight LPL peptide (TAT- MARGSVSDEE, denoted as an inhibitory LPL peptide) attenuated the formation of NSZs and impaired bone resorption in vitro in osteoclasts. Also, the genetic deletion of LPL in mice demonstrated decreased eroded perimeters and increased trabecular bone density. In the present study, we hypothesized that targeting LPL with the inhibitory LPL peptide in vivo could reduce osteoclast function and increase bone density in a mice model of low bone mass. We injected aging C57BL/6 female mice (36 weeks old) subcutaneously with the inhibitory and scrambled peptides of LPL for 14 weeks. Micro-CT and histomorphometry analyses demonstrated an increase in trabecular bone density of femoral and tibial bones with no change in cortical thickness in mice injected with the inhibitory LPL peptide. A reduction in the serum levels of CTX-1 peptide suggests that the increase in bone density is associated with a decrease in osteoclast function. No changes in bone formation rate and mineral apposition rate, and the serum levels of P1NP indicate that the inhibitory LPL peptide does not affect osteoblast function. Our study shows that the inhibitory LPL peptide can block osteoclast function without impairing the function of osteoblasts. LPL peptide could be developed as a prospective therapeutic agent to treat osteoporosis.

Simvastatin loaded chitosan guided bone regeneration membranes stimulate bone healing

AUTHORS

Vishnu Priya Murali, Fernanda D. Guerra, Najib Ghadri, James M. Christian, Sidney H. Stein, Jessica A. Jennings, Richard A. Smith, Joel D. Bumgardner

ABSTRACT

Background and Objective

Electrospun chitosan membranes (ESCM) modified with short-chain fatty acids have the ability to control the release of simvastatin (SMV), an anti-cholesterol drug with osteogenic potential, for guided bone regeneration (GBR) applications. This study evaluated in vivo osteogenic effects of rapid short release of SMV (4 weeks) vs long sustained release (8 weeks) from acetic anhydride (AA)—and hexanoic anhydride (HA)-modified ESCMs, respectively.

Methods

AA ESCMs loaded with 10 or 50 µg SMV and HA ESCMs loaded with 50 µg SMV were evaluated for biocompatibility and bone formation at 4 and 8 weeks, in 5 mm critical size rat calvarial defects, using histological evaluation and micro-CT analysis.

Results

No severe inflammatory response was noticed around the ESCMs. Less hydrophobic AA membranes showed signs of resorption by week 4 and were almost completely resorbed by week 8 whereas the more hydrophobic HA membranes resorbed slowly, remaining intact over 8 weeks. In micro-CT analysis, 10 µg SMV-loaded AA membranes did not show significant bone formation as compared to non-loaded AA membranes at either evaluation time points. 50 µg SMV-loaded AA membranes stimulated significantly more bone formation than non-loaded AA membranes by week 4 (%bone = 31.0 ± 5.9% (AA50) vs 18.5 ± 13.7% (AA0)) but showed no difference at week 8. HA membranes with 50 µg SMV showed significantly more bone formation as compared to corresponding non-loaded membranes by week 8 (%bone = 61.7 ± 8.9% (HA50) vs 33.9 ± 29.7% (HA0)), though such an effect was not significant at week 4.

Conclusion

These results indicate that modified ESCMs may be used to control the release of SMV and promote bone healing in GBR applications.

Experimental Study of the Effects of Hypoxia Simulator on Osteointegration of Titanium Prosthesis in Osteoporotic Rats

AUTHORS

Jiangfeng Liu, Huijun Kang, Jiangfeng Lu, Yike Dai, Fei Wang

ABSTRACT

Purpose: Poor osseointegration is the key reason for implant failure after arthroplasty, whether in osteoporotic or normal bone conditions. To date, osseointegration remains a major challenge. Recent studies have shown that deferoxamine(DFO) can accelerate osteogenesis by activation of the hypoxia signal pathway. The purpose of this study is to test the following hypothesis: after knee replacement, intra-articular injection of DFO will promote osteogenesis and osseointegration with titanium prosthesis in the bones of osteoporotic rats.

Materials and Methods: 90 female sprague-dawley rats were used for the experiment. Ovariectomy and knee arthroplasty were performed. Then, the rats were randomly divided into DFO and control group(n=40 per group). The two groups were treated by intraarticular injection of DFO and saline respectively. After 2 weeks, polymerase chain reaction(PCR) and immunohistochemistry were used to evaluate the levels of HIF-1a, VEGF and CD31. After 12 weeks, the specimens were examined by micro CT, biomechanics and histopathology to evaluate osteogenesis and osseointegration.

Results: The results of PCR showed mRNA levels of VEGF and CD31 in DFO group were significantly higher than those in control group. The immunohistochemistry results indicated positive cell expressions of HIF-1a, VEGF and CD31 in DFO group were also higher. Compared to control group, the microCT parameters of BMD, BV/TV, TB.N, TB.Th were significantly higher. The maximal pull-out force and the bone-to-implant contact (BIC) value were also higher .

Conclusions: The local administration of DFO which is used to activate HIF-1a signaling pathway can promote osteogenesis and osseointegration with the prosthesis in osteoporotic bone.

Three-dimensional-printed individualized porous implants: A new “implant-bone” interface fusion concept for large bone defect treatment

AUTHORS

Teng Zhang, Qingguang Wei, Hua Zhou, Zehao Jing, Xiaoguang Liu, Yufeng Zheng, Hong Cai, Feng Wei, Liang Jiang, Miao Yu, Yan Cheng, Daoyang Fan, Wenhao Zhou, Xinhong Lin, Huijie Leng, Jian Li, Xinyu Li, Caimei Wang, Yun Tian, Zhongjun Liu

ABSTRACT

Bone defect repairs are based on bone graft fusion or replacement. Current large bone defect treatments are inadequate and lack of reliable technology. Therefore, we aimed to investigate a simple technique using three-dimensional (3D)-printed individualized porous implants without any bone grafts, osteoinductive agents, or surface biofunctionalization to treat large bone defects, and systematically study its long-term therapeutic effects and osseointegration characteristics. Twenty-six patients with large bone defects caused by tumor, infection, or trauma received treatment with individualized porous implants; among them, three typical cases underwent a detailed study. Additionally, a large segmental femur defect sheep model was used to study the osseointegration characteristics. Immediate and long-term biomechanical stability was achieved, and the animal study revealed that the bone grew into the pores with gradual remodeling, resulting in a long-term mechanically stable implant-bone complex. Advantages of 3D-printed microporous implants for the repair of bone defects included 1) that the stabilization devices were immediately designed and constructed to achieve early postoperative mobility, and 2) that osseointegration between the host bone and implants was achieved without bone grafting. Our osseointegration method, in which the “implant-bone” interface fusion concept was used instead of “bone-bone” fusion, subverts the traditional idea of osseointegration.

The Effects of Photobiomodulation on Leukocyte and Platelet-Rich Fibrin as Barrier Membrane on Bone Regeneration: An Experimental Animal Study

AUTHORS

Seren Surmeli Baran, Andy Temmerman, Fariz Salimov, Onur Ucak Turer, Tugce Sapmaz, Mehmet Cenk Haytac, and Mustafa Ozcan

ABSTRACT

Objective: To compare the effects of leukocyte and platelet-rich fibrin (L-PRF) and photobiomodulation therapy (PBMT)-applied L-PRF (PBMT/L-PRF) as barrier membranes on new bone formation (BV/TV) for the treatment of critical-sized bone defects.

Materials and methods: The right iliac crests of five sheep were used in this experimental animal study. Eight critical-sized defects were surgically created in each sheep and a total of 40 defects were obtained. A deproteinized bovine bone graft was placed in all defects, and the defects were divided into four groups to be covered with L-PRF membrane, PBMT/L-PRF membrane, collagen membrane, or left uncovered as controls. Animals were sacrificed at 1 month. The sections obtained were histomorphometrically analyzed.

Results: The results showed that the collagen group presented significantly higher values for main bone healing parameters (BV/TV, bone volume, and bone surface; p < 0.05). The PBMT/L-PRF group presented higher values than the L-PRF group and controls for these parameters though not statistically significant (p > 0.05).

Conclusions: The findings show that PBMT may provide additional regenerative properties to L-PRF when used as barrier membranes. However, these results did not reach the collagen membranes, which warrants further studies for adapting the laser parameters to increase regenerative capacity of L-PRF.