Injectable sericin based nanocomposite hydrogel for multi-modal imaging-guided immunomodulatory bone regeneration

AUTHORS

Li-Bo Jiang, Sheng-Long Ding, Wang Ding, Di-Han Su, Fang-Xue Zhang, Tai-Wei Zhang, Xiao-Fan Yin, Lan Xiao, Yu-Lin Li, Feng-Lai Yuan, Jian Dong

ABSTRACT

Irregular bone defects, where the inflammation and immune microenvironment confronted with implanted biomaterials, remain a prominent challenge for bone regeneration. In this study, we fabricated an injectable alginate/sericin/graphene oxide (Alg/Ser/GO) hydrogel based on the Alg–Tyramine framework with HRP/H2O2 enzymatic crosslinking. This hydrogel exhibited bioimaging property and controlled degradation behavior upon releasing sericin and GO. Importantly, synergistic effects on bone regeneration between sericin and GO were demonstrated. GO significantly enhanced the spreading, osteogenic differentiation, and mineralization of encapsulated rat BMSCs, whereas the released sericin promoted M2 polarization and migration via the NF-κB and MAPK pathways. The M2 polarization of macrophages induced osteogenic differentiation of BMSCs via several secreted cytokines. Both in vivo and in vitro experiments showed that the Alg/Ser/GO hydrogel induced macrophage infiltration into the surrounding tissues and inhibited inflammation and fibrous capsule thickening. Last, the injected Alg/Ser/GO hydrogels with BMSCs promptly repaired established distal femoral defects in rats. Therefore, the fabricated Alg/Ser/GO hydrogel, along with macrophages and BMSCs, is a promising biomaterial for bone healing, especially the irregular bone defects.

Anti-RANKL monoclonal antibody and bortezomib prevent mechanical unloading-induced bone loss

AUTHORS

Yi Ding, Yu Cui, Xi Yang, Xiaolu Wang, Guangzhao Tian, Jiang Peng, Bo Wu, Li Tang, Chun-Ping Cui & Lingqiang Zhang

ABSTRACT

Introduction

Bone loss is a major health concern for astronauts during long-term spaceflight and for patients during prolonged bed rest or paralysis. It is essential to develop therapeutic strategies to combat the bone loss occurring in people afflicted with disuse atrophy on earth as well as in astronauts in space, especially during prolonged missions. Although several drugs have been demonstrated for treating postmenopausal osteoporosis or bone-related diseases, their effects on microgravity-induced bone loss are still unclear.

Materials and methods

Here, we employed the hindlimb-unloading (HLU) tail suspension model and compared the preventive efficiencies of five agents including alendronate (ALN), raloxifene (Rox), teriparatide (TPTD), anti-murine RANKL monoclonal antibody (anti-RANKL) and proteasome inhibitor bortezomib (Bzb) on mechanical unloading-induced bone loss. Bone mineral density (BMD) was measured by quantitative computed tomography. The osteoblastic and osteoclastic activity were measured by serum ELISA, histology analysis, and histomorphometric analysis.

Results

Compared to the control, ALN and anti-RANKL antibody could restore bone mass close to sham levels by inhibiting bone resorption. Bzb could increase the whole bone mass and strength by inhibiting bone resorption and promoting bone formation simultaneously. Meanwhile, Rox did not affect bone loss caused by HLU. TPTD stimulated cortical bone formation but the total bone mass was not increased significantly.

Conclusions

We demonstrated for the first time that anti-RANKL antibody and Bzb had a positive effect on preventing mechanical unloading-induced bone loss. This finding puts forward the potential use of anti-RANKL and Bzb on bone loss therapies or prophylaxis of astronauts in spaceflight.

WNT7B overexpression rescues bone loss caused by glucocorticoids in mice

AUTHORS

Hong Chen, Fangfang Song, Fanxin Long

ABSTRACT

Glucocorticoids, widely prescribed for anti-inflammatory and immunosuppressive purposes, are the most common secondary cause for osteoporosis and related fractures. Current anti-resorptive and anabolic therapies are insufficient for treating glucocorticoid-induced osteoporosis due to contraindications or concerns of side effects. Glucocorticoids have been shown to disrupt Wnt signaling in osteoblast-lineage cells, but the efficacy for Wnt proteins to restore bone mass after glucocorticoid therapy has not been examined. Here by using two mouse genetic models wherein WNT7B expression is temporally activated by either tamoxifen or doxycycline in osteoblast-lineage cells, we show that WNT7B recovers bone mass following glucocorticoid-induced bone loss, thanks to increased osteoblast number and function. However, WNT7B overexpression in bone either before or after glucocorticoid treatments does not ameliorate the abnormal accumulation of body fat. The study demonstrates a potent bone anabolic function for WNT7B in countering glucocorticoid-induced bone loss.

Type 1 diabetic Akita mice have low bone mass and impaired fracture healing

AUTHORS

Pei Hu, Jennifer A. McKenzie, Evan G. Buettmann, Nicole Migotsky, Michael J. Gardner, Matthew J.Silva

ABSTRACT

Type 1 diabetes (T1DM) impairs bone formation and fracture healing in humans. Akita mice carry a mutation in one allele of the insulin-2 (Ins2) gene, which leads to pancreatic beta cell dysfunction and hyperglycemia by 5–6 weeks age. We hypothesized that T1DM in Akita mice is associated with decreased bone mass, weaker bones, and impaired fracture healing. Ins2 ± (Akita) and wildtype (WT) males were subjected to femur fracture at 18-weeks age and healing assessed 3–21 days post-fracture. Non-fractured left femurs were assessed for morphology (microCT) and strength (bending or torsion) at 19–21 weeks age. Fractured right femurs were assessed for callus mechanics (torsion), morphology and composition (microCT and histology) and gene expression (qPCR). Both Akita and WT mice gained weight from 3 to 18 weeks age, but Akita mice weighed less starting at 5 weeks (−5.2%, p < 0.05). At 18–20 weeks age Akita mice had reduced serum osteocalcin (−30%), cortical bone area (−16%), and thickness (−17%) compared to WT, as well as reduced cancellous BV/TV (−39%), trabecular thickness (−23%) and vBMD (−31%). Mechanical testing of non-fractured femurs showed decreased structural (stiffness, ultimate load) and material (ultimate stress) properties of Akita bones. At 14 and 21 days post fracture Akita mice had a significantly smaller callus than WT mice (~30%), with less cartilage and bone area. Assessment of torsional strength showed a weaker callus in Akita mice with lower stiffness (−42%), maximum torque (−44%) and work to fracture (−44%). In summary, cortical and cancellous bone mass were reduced in Akita mice, with lower bone mechanical properties. Fracture healing in Akita mice was impaired by T1DM, with a smaller, weaker fracture callus due to decreased cartilage and bone formation. In conclusion, the Akita mouse mimics some of the skeletal features of T1DM in humans, including osteopenia and impaired fracture healing, and may be useful to test interventions.

A functional motif of long noncoding RNA Nron against osteoporosis

AUTHORS

Fujun Jin, Junhui Li, Yong-Biao Zhang, Xiangning Liu, Mingxiang Cai, Meijing Liu, Mengyao Li, Cui Ma, Rui Yue, Yexuan Zhu, Renfa Lai, Zuolin Wang, Xunming Ji, Huawei Wei, Jun Dong, Zhiduo Liu, Yifei Wang, Yao Sun & Xiaogang Wang

ABSTRACT

Long noncoding RNAs are widely implicated in diverse disease processes. Nonetheless, their regulatory roles in bone resorption are undefined. Here, we identify lncRNA Nron as a critical suppressor of bone resorption. We demonstrate that osteoclastic Nron knockout mice exhibit an osteopenia phenotype with elevated bone resorption activity. Conversely, osteoclastic Nron transgenic mice exhibit lower bone resorption and higher bone mass. Furthermore, the pharmacological overexpression of Nron inhibits bone resorption, while caused apparent side effects in mice. To minimize the side effects, we further identify a functional motif of Nron. The delivery of Nron functional motif to osteoclasts effectively reverses bone loss without obvious side effects. Mechanistically, the functional motif of Nron interacts with E3 ubiquitin ligase CUL4B to regulate ERα stability. These results indicate that Nron is a key bone resorption suppressor, and the lncRNA functional motif could potentially be utilized to treat diseases with less risk of side effects.

Functional interaction between Wnt and Bmp signaling in periosteal bone growth

AUTHORS

Deye Song, Guangxu He, Yu Shi, Jiangdong Ni & Fanxin Long

ABSTRACT

Wnt and Bmp proteins are well known to regulate bone development and homeostasis. Although both signals are extensively studied, their potential interaction in vivo is less well understood. Previous studies have shown that deletion of Bmpr1a, a type I receptor for Bmp signaling, results in excessive trabecular bone formation while diminishing periosteal bone growth. Moreover, forced-expression of the Wnt antagonist Sost suppresses the overgrowth of trabecular bone caused by Bmpr1a deletion, thus implicating hyperactive Wnt signaling in the excessive trabecular bone formation. However, it remains uncertain whether Wnt and Bmp signaling interacts in regulating the periosteal bone growth. Here we show that multiple Wnt genes are markedly suppressed in the cortical bone without Bmpr1a. Importantly, overexpression of Wnt7b fully rescues periosteal bone growth in the Bmpr1a-deficient mice. Thus, pharmacological activation of Wnt signaling can restore normal bone size without intact Bmp signaling.