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Anabolic Effects of a Novel Simvastatin Derivative on Treating Rat Bone Defects.

ABSTRACT: Large bone defects may develop fracture nonunion, leading to disability and psychosocial burdens. Bone grafting with anabolic agents is a good autografting alternative. Simvastatin, as a cholesterol-lowering agent worldwide, is proven to enhance osteogenesis. Considering its dose-dependent adverse effects, we developed a simvastatin derivative, named KMUHC-01, which has bone anabolic capacity and lower cytotoxicity than simvastatin. We hypothesize that KMUHC-01 could help bone formation in bone-defect animal models. We used rat models of critical calvarial and long-bone defects to evaluate the effects of KMUHC-01 and simvastatin on biological changes at the bone defect through histology, immunohistology, and mechanical testing using three-point bending and evaluated the new bone formation microstructure through microcomputed tomography analysis. The newly formed bone microstructure at the calvarial defect site showed a significantly improved trabecular bone volume in the KMUHC-01 1-μM group compared with that in the control and simvastatin groups. The biomechanical study revealed a significantly increased maximal strength in the KMUHC-01 1-μM group compared with that in the control group. KUMHC-01, as a simvastatin derivative, showed a great anabolic effect in promoting bone defect healing. However, further studies will be conducted to prove the bioavailability and bone-forming efficacy of KMUHC-01 via systemic administration.

SUBMITTER: Lee TC

PROVIDER: S-EPMC9405916 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Anabolic Effects of a Novel Simvastatin Derivative on Treating Rat Bone Defects.

Lee Tien-Ching TC Chen Hui-Ting HT Tai I-Chun IC Kao Li-Ting LT Hung Ming-Hsin MH Chen Chung-Hwan CH Fu Yin-Chih YC Wang Yan-Hsiung YH Kao Chih-Ming CM Chang Je-Ken JK Ho Mei-Ling ML

Biomedicines 20220808 8

Large bone defects may develop fracture nonunion, leading to disability and psychosocial burdens. Bone grafting with anabolic agents is a good autografting alternative. Simvastatin, as a cholesterol-lowering agent worldwide, is proven to enhance osteogenesis. Considering its dose-dependent adverse effects, we developed a simvastatin derivative, named KMUHC-01, which has bone anabolic capacity and lower cytotoxicity than simvastatin. We hypothesize that KMUHC-01 could help bone formation in bone- ...[more]

PMID: 36009462

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Project description:Investigations of teriparatide (recombinant parathyroid hormone [rPTH]) as a potential treatment for critical defects have demonstrated the predicted anabolic effects on bone formation, and significant non-anabolic effects on healing via undefined mechanisms. Specifically, studies in murine models of structural allograft healing demonstrated that rPTH treatment increased angiogenesis (vessels <30 μm), and decreased arteriogenesis (>30 μm) and mast cell numbers, which lead to decreased fibrosis and accelerated healing. To better understand these non-anabolic effects, we interrogated osteogenesis, vasculogenesis, and mast cell accumulation in mice randomized to placebo (saline), rPTH (20 μg/kg/2 days), or the mast cell inhibitor sodium cromolyn (SC) (24 μg/kg/ 2days), via longitudinal micro-computed tomography (μCT) and multiphoton laser scanning microscopy (MPLSM), in a critical calvaria defect model. μCT demonstrated that SC significantly increased defect window closure and new bone volume versus placebo (p < 0.05), although these effects were not as great as rPTH. Interestingly, both rPTH and SC have similar inhibitory effects on arteriogenesis versus placebo (p < 0.05) without affecting total vascular volume. MPLSM time-course studies in untreated mice revealed that large numbers of mast cells were detected 1 day postoperation (43 ± 17), peaked at 6 days (76 ± 6), and were still present in the critical defect at the end of the experiment on day 30 (20 ± 12). In contrast, angiogenesis was not observed until day 4, and functional vessels were first observed on 6 days, demonstrating that mast cell accumulation precedes vasculogenesis. To confirm a direct role of mast cells on osteogenesis and vasculogenesis, we demonstrated that specific diphtheria toxin-α deletion in Mcpt5-Cre-iDTR mice results in similar affects as SC treatment in WT mice. Collectively, these findings demonstrate that mast cells inhibit bone defect healing by stimulating arteriogenesis associated with fibrotic scaring, and that an efficacious non-anabolic effect of rPTH therapy on bone repair is suppression of arteriogenesis and fibrosis secondary to mast cell inhibition. © 2017 American Society for Bone and Mineral Research.

Project description:Tissue engineering has recently become available as a treatment procedure for bone augmentation. However, this procedure has several problems, such as high capital investment and expensive cell culture, complicated safety and quality management issues regarding cell handling, and patient problems with the invasive procedure of cell collection. Moreover, it was reported that stem cells secrete many growth factors and chemokines during their cultivation, which could affect cellular characteristics and behavior. This study investigated the effect of stem-cell-cultured conditioned media on bone regeneration. Cultured conditioned media from human bone marrow-derived mesenchymal stem cells (MSC-CM) enhanced the migration, proliferation, and expression of osteogenic marker genes, such as osteocalcin and Runx2, of rat MSCs (rMSCs) in vitro. MSC-CM includes cytokines such as insulin-like growth factor-1 and vascular endothelial growth factor. In vivo, a prepared bone defect of a rat calvarial model was implanted in five different rat groups using one of the following graft materials: human MSCs/agarose (MSCs), MSC-CM/agarose (MSC-CM), Dulbecco's modified Eagle's medium without serum [DMEM(-)]/agarose [DMEM(-)], PBS/agarose (PBS), and defect only (Defect). After 4 and 8 weeks, implant sections were evaluated using microcomputed tomography (micro-CT) and histological analysis. Micro-CT analysis indicated that the MSC-CM group had a greater area of newly regenerated bone compared with the other groups (p<0.05) and histological analysis at 8 weeks indicated that the newly regenerated bone bridge almost covered the defect. Interestingly, the effects of MSC-CM were stronger than those of the MSC group. In vivo imaging and immunohistochemical staining of transgenic rats expressing green fluorescent protein also showed that migration of rMSCs to the bone defect in the MSC-CM group was greater than in the other groups. These results demonstrated that MSC-CM can regenerate bone through mobilization of endogenous stem cells. The use of stem-cell-cultured conditioned media for bone regeneration is a unique concept that utilizes paracrine factors of stem cells without cell transplantation.

Dataset Information

Anabolic Effects of a Novel Simvastatin Derivative on Treating Rat Bone Defects.

Publications

Anabolic Effects of a Novel Simvastatin Derivative on Treating Rat Bone Defects.

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