Author Correction: NELL-1 in the treatment of osteoporotic bone loss.
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ABSTRACT:
SUBMITTER: James AW
PROVIDER: S-EPMC7806913 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Author Correction: NELL-1 in the treatment of osteoporotic bone loss.
James Aaron W AW Shen Jia J Zhang Xinli X Asatrian Greg G Goyal Raghav R Kwak Jin H JH Jiang Lin L Bengs Benjamin B Culiat Cymbeline T CT Turner A Simon AS Seim Howard B HB Wu Benjamin M BM Lyons Karen K Adams John S JS Ting Kang K Soo Chia C
Nature communications 20210113 1
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Project description:NELL-1 is a secreted, osteoinductive protein whose expression rheostatically controls skeletal ossification. Overexpression of NELL-1 results in craniosynostosis in humans and mice, whereas lack of Nell-1 expression is associated with skeletal undermineralization. Here we show that Nell-1-haploinsufficient mice have normal skeletal development but undergo age-related osteoporosis, characterized by a reduction in osteoblast:osteoclast (OB:OC) ratio and increased bone fragility. Recombinant NELL-1 binds to integrin β1 and consequently induces Wnt/β-catenin signalling, associated with increased OB differentiation and inhibition of OC-directed bone resorption. Systemic delivery of NELL-1 to mice with gonadectomy-induced osteoporosis results in improved bone mineral density. When extended to a large animal model, local delivery of NELL-1 to osteoporotic sheep spine leads to significant increase in bone formation. Altogether, these findings suggest that NELL-1 deficiency plays a role in osteoporosis and demonstrate the potential utility of NELL-1 as a combination anabolic/antiosteoclastic therapeutic for bone loss.
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Project description:BackgroundVertebral compression fractures related to osteoporosis greatly afflict the aging population. One of the most commonly used therapy today is balloon kyphoplasty. However, this treatment is far from ideal and is associated with significant side effects. NELL-1, an osteoinductive factor that possesses both pro-osteogenic and anti-osteoclastic properties, is a promising candidate for an alternative to current treatment modalities. This study utilizes the pro-osteogenic properties of recombinant human NELL-1 (rhNELL-1) in lumbar spine vertebral defect model in osteoporotic sheep.MethodsOsteoporosis was induced through ovariectomy, dietary depletion of calcium and vitamin D, and steroid administration. After osteoporotic induction, lumbar vertebral body defect creation was performed. Sheep were randomly implanted with the control vehicle, comprised of hyaluronic acid (HA) with hydroxyapatite-coated β-tricalcium phosphate (β-TCP), or the treatment material of rhNELL-1 protein lyophilized onto β-TCP mixed with HA. Analysis of lumbar spine defect healing was performed by radiographic, histologic, and computer-simulated biomechanical testing.ResultsrhNELL-1 treatment significantly increased lumbar spine bone formation, as determined by bone mineral density, % bone volume, and mean cortical width as assessed by micro-computed tomography. Histological analysis revealed a significant increase in bone area and osteoblast number and decrease in osteoclast number around the implant site. Computer-simulated biomechanical analysis of trabecular bone demonstrated that rhNELL-1-treatment resulted in a significantly more stress-resistant composition.ConclusionOur findings suggest rhNELL-1-based vertebral implantation successfully improved cortical and cancellous bone regeneration in the lumbar spine of osteoporotic sheep. rhNELL-1-based bone graft substitutes represent a potential new local therapy.
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Project description:Over 10 million Americans have osteoporosis, and is the predominant cause of fractures in the elderly. Treatment of fractures in the setting of osteoporosis is complicated by a suboptimal bone regenerative response due to a decline in the number of osteoblasts, their function, and survival. Consequently, an osteogenic therapeutic to prevent and treat fractures in patients with osteoporosis is needed. Nel-like molecule-1 (NELL-1), a novel osteoinductive growth factor, has been shown to promote bone regeneration. In this study, we aim to demonstrate the capacity of recombinant NELL-1 to prevent ovariectomy (OVX)-induced osteoporosis in a senile rat model. Ten-month-old female Sprague-Dawley rats underwent either sham surgery or OVX. Subsequently, 50 ?L of 600 ?g/mL NELL-1 lyophilized onto a 0-50-?m tricalcium phosphate (TCP) carrier was injected into the femoral bone marrow cavity while phosphate-buffered saline (PBS) control was injected into the contralateral femur. Our microcomputed tomography results showed that OVX+PBS/TCP control femurs showed a continuous decrease in the bone volume (BV) and bone mineral density (BMD) from 2 to 8 weeks post-OVX. In contrast, OVX+NELL-1/TCP femurs showed resistance to OVX-induced bone resorption showing BV and BMD levels similar to that of SHAM femurs at 8 weeks post-OVX. Histology showed increased endosteal-woven bone, as well as decreased adipocytes in the bone marrow of NELL-1-treated femurs compared to control. NELL-1-treated femurs also showed increased immunostaining for bone differentiation markers osteopontin and osteocalcin. These findings were validated in vitro, in which addition of NELL-1 in OVX bone marrow stem cells resulted in increased osteogenic differentiation. Thus, NELL-1 effectively enhances in situ osteogenesis in the bone marrow, making it potentially useful in the prevention and treatment of osteoporotic fractures.
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Project description:Bone remodeling is a renewal process regulated by bone synthesis (osteoblasts) and bone destruction (osteoclasts). A previous study demonstrated that Lycii radicis cortex (LRC) extract inhibited ovariectomized (OVX)-induced bone loss in mice. This study investigated the anti-osteoporotic effects of bioactive constituent(s) from the LRC extract. The effective compound(s) were screened, and a single compound, scopolin, which acts as a phytoalexin, was chosen as a candidate component. Scopolin treatment enhanced alkaline phosphatase activity and increased mineralized nodule formation in MC3T3-E1 pre-osteoblastic cells. However, osteoclast differentiation in primary-cultured monocytes was reduced by treatment with scopolin. Consistently, scopolin treatment increased osteoblast differentiation in the co-culture of monocytes (osteoclasts) and MC3T3-E1 (osteoblast) cells. Scopolin treatment prevented bone mineral density loss in OVX-induced osteoporotic mice. These results suggest that scopolin could be a therapeutic bioactive constituent for the treatment and prevention of osteoporosis.
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Project description:Extracellular adenosine has been shown to play a key role in maintaining bone health and could potentially be used to treat bone loss. However, systemic administration of exogenous adenosine to treat bone disorders remains a challenge due to the ubiquitous presence of adenosine receptors in different organs and the short half-life of adenosine in circulation. Towards this, we have developed a bone-targeting nanocarrier and determined its potential for systemic administration of adenosine. The nanocarrier, synthesized via emulsion suspension photopolymerization, is comprised of hyaluronic acid (HA) copolymerized with phenylboronic acid (PBA), a moiety that can form reversible bonds with adenosine. The bone binding affinity of the nanocarrier was achieved by alendronate (Aln) conjugation. Nanocarriers functionalized with the alendronate (Aln-NC) showed a 45% higher accumulation in the mice vertebrae in vivo compared to those lacking alendronate molecules (NCs). Systemic administration of adenosine via bone-targeting nanocarriers (Aln-NC) attenuated bone loss in ovariectomized (OVX) mice. Furthermore, bone tissue of mice treated with adenosine-loaded Aln-NC displayed trabecular bone characteristics comparable to healthy controls as shown by microcomputed tomography, histochemical staining, bone labeling, and mechanical strength. Overall, our results demonstrate the use of a bone-targeting nanocarrier towards systemic administration of adenosine and its application in treating bone degenerative diseases such as osteoporosis.
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Project description:Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1's osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).
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Project description:Osteoporosis (OP) is a systemic skeletal disorder, manifesting with a reduction in bone mass and deterioration of the microarchitecture. Mesenchymal stem cells (MSCs) have an innate ability to differentiate into several cell types, including osteoblasts (OB). Ginsenoside Rb1 (GRb1) is an ethanol extract from ginseng and contains a highly concentrated form of ginsenoside. GRb1 shows extensive beneficial health effects such as anti-oxidative and anti-inflammatory functions, modulating the immune system and inhibiting osteoclastogenesis. We hypothesized that GRb1 can promote MSC differentiation into OBs and inhibit bone loss. In the present study, we aimed to address two questions: (1) Will GRb1 have a positive effect on osteogenic differentiation of MSCs? and (2) Will GRb1 halt bone loss in ovariectomized (OVX) rats? We investigated the effects of GRb1 on viability and osteogenic differentiation of rat mesenchymal stem cells (rMSCs). Our results showed that GRb1 at concentrations of 10-8 M and 10-6 M can increase alkaline phosphatase activity, mineralization and the expression of osteogenic related proteins, such as osteopontin and osteoprotegerin, while incubating rMSCs with osteogenic induction medium and GRb1. Adding GRb1 into the medium can prevent rMSCs from Oxidative damage at the concentration of 25μM H2O2. Furthermore, 40 4-month-old rats were assigned to 5 groups(8 rats per group): the basal group, the sham group, the OVX group, the high dose of GRb1 group (6 mg/kg/day) and the low dose of GRb1 group (3 mg/kg/day). Rats recrived treatment 3days after surgery and last for 14 weeks. Examinations included serum analysis, mechanical testing, Masson-Goldner trichrome staining and bone histomorphometry analysis. The results showed that OVX can lead to dyslipidemia and excessive oxidative stress, whereas GRb1 cannot significantly halt dyslipidemia and excessive oxidative stress in OVX rats. In addition, the bone density of the lumbar vertebra and femur were decreased significantly in the OVX rats, and GRb1 could not inhibit bone loss. Bone histomorphometry analysis showed that the number and width of bone trabecula of the tibia were reduced in OVX rats, and GRb1 could not prevent their occurrence. A bone biomechanics assay showed that GRb1 cannot improve the ability of bone structure to resist fracture of the femur in OVX rats. The current study demonstrated that GRb1 has an obvious effect on osteogenic differentiation in rMSCs but no obvious effect on bone loss in OVX rats. These findings indicate GRb1 has a positive effect on rMSCs but does not have an effect on bone loss in OVX rats at the concentration we used.
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