Selective Retinoic Acid Receptor γ Antagonist 7C is a Potent Enhancer of BMP-Induced Ectopic Endochondral Bone Formation

Abstract

Bone morphogenetic proteins (BMPs) have been clinically applied for induction of bone formation in musculoskeletal disorders such as critical-sized bone defects, nonunions, and spinal fusion surgeries. However, the use of supraphysiological doses of BMP caused adverse events, which were sometimes life-threatening. Therefore, safer treatment strategies for bone regeneration have been sought for decades. Systemic administration of a potent selective antagonist of retinoic acid nuclear receptor gamma (RARγ) (7C) stimulated BMP-induced ectopic bone formation. In this study, we developed 7C-loaded poly lactic nanoparticles (7C-NPs) and examined whether local application of 7C enhances BMP-induced bone regeneration. The collagen sponge discs that absorbed recombinant human (rh) BMP-2 were implanted into the dorsal fascia of young adult mice to induce ectopic bone. The combination of rhBMP-2 and 7C-NP markedly increased the total bone volume and thickness of the bone shell of the ectopic bone in a dose-dependent manner compared to those with rhBMP-2 only. 7C stimulated sulfated proteoglycan production, expression of chondrogenic marker genes, and Sox9 reporter activity in both chondrogenic cells and MSCs. The findings suggest that selective RARγ antagonist 7C or the related compounds potentiate the bone inductive ability of rhBMP-2, as well as support any future research to improve the BMP-2 based bone regeneration procedures in a safe and efficient manner.

Advances in bone regeneration with growth factors for spinal fusion: A literature review

“…Systemic administration of an RARγ antagonist promoted BMP-induced ectopic bone formation in mice [52] . Furthermore, when 7C, a synthetic RARγ antagonist, was loaded into polylactide nanoparticles (NPs), local administration of 7C-NPs significantly increased BMP-induced bone formation in a murine ectopic bone formation model [54] . Histological analysis showed that 7C particularly enhanced cartilage formation in the early stage of BMP-induced endochondral bone formation.…”

“…Thus, since BMP is a potent inducer of endochondral bone formation in vivo , an approach that assists cartilage formation would be useful for BMP-induced bone regeneration. In endochondral bone formation, the initially formed cartilage tissue serves as a template for bone replacement [54] , [55] , [56] . A larger cartilage template allows for larger bone regeneration [ 54 , 56 ].…”

“…In endochondral bone formation, the initially formed cartilage tissue serves as a template for bone replacement [54] , [55] , [56] . A larger cartilage template allows for larger bone regeneration [ 54 , 56 ].…”

“…However, rapidly released BMPs cause bone formation not only at the target site but also in the surrounding area (ectopic ossification at unintended sites), resulting in poor quality new bone with abundant fatty marrow in the central region [ 60 , 61 ]. In addition, burst release is more likely to produce side effects such as concentration-dependent inflammatory reactions [ 54 , 62 ]. In contrast, sustained release of BMPs attenuates the spread of the inflammatory response to the surroundings in the early stages of the bone formation process, resulting in the induction of new bone that does not differ substantially from the size of target sites [ 62 , 63 ].…”

Cellular senescence by loss of Men1 in osteoblasts is critical for age-related osteoporosis

“…Bone morphogenic protein (BMP) is known to activate mTORC1 and regulate cellular senescence [21][22][23] . A previous report showed that the transplantation of a BMP-containing collagen sponge allowed us to observe the bone formation capacity 24 . We hypothesized that the effects of osteoblast senescence would be enhanced by conditions of BMP-induced bone formation.…”