Interleukin-1β modulates endochondral ossification by human adult bone marrow stromal cells

Abstract

Inflammatory cytokines present in the milieu of the fracture site are important modulators of bone healing. Here we investigated the effects of interleukin-1β (IL-1β) on the main events of endochondral bone formation by human bone marrow mesenchymal stromal cells (BM-MSC), namely cell proliferation, differentiation and maturation/ remodelling of the resulting hypertrophic cartilage. Low doses of IL-1β (50 pg/mL) enhanced colony-forming unitsfibroblastic (CFU-f) and-osteoblastic (CFU-o) number (up to 1.5-fold) and size (1.2-fold) in the absence of further supplements and glycosaminoglycan accumulation (1.4-fold) upon BM-MSC chondrogenic induction. In osteogenically cultured BM-MSC, IL-1β enhanced calcium deposition (62.2-fold) and BMP-2 mRNA expression by differential activation of NF-κB and ERK signalling. IL-1β-treatment of BM-MSC generated cartilage resulted in higher production of MMP-13 (14.0-fold) in vitro, mirrored by an increased accumulation of the cryptic cleaved fragment of aggrecan, and more efficient cartilage remodelling/resorption after 5 weeks in vivo (i.e., more TRAP positive cells and bone marrow, less cartilaginous areas), resulting in the formation of mature bone and bone marrow after 12 weeks. In conclusion, IL-1β finely modulates early and late events of the endochondral bone formation by BM-MSC. Controlling the inflammatory environment could enhance the success of therapeutic approaches for the treatment of fractures by resident MSC and as well as improve the engineering of implantable tissues.

Engineering of a functional bone organ through endochondral ossification

“…In line with the known effect on growth plate and fracture callus cartilage (16), in our model IL-1β induced (i) enhanced MMP-13-mediated endogenous ECM preprocessing; (ii) enhanced host osteoclastmediated ECM remodeling by increased M-CSF levels and RANKL/OPG ratios; (iii) faster vascularization, despite a minimal reduction in VEGF content (15); and (iv) larger regions of BM, possibly because of an increased synthesis of SDF1, IL-8, M-CSF, and MCP-1. Instead, IL-1β did not induce a reduction of bone mass by increased bone resorption (24), because its administration was temporally confined to the phase preceding bone matrix deposition.…”

“…Human MSCs were thus seeded into collagen-based scaffolds (8-mm diameter, 2 mm thick), as templates for tissue development. During the last 2 wk, culture medium was further supplemented with IL-1β (50 pg/mL) to accelerate remodeling of a large cartilage mass (15). The resulting constructs resembled most features of the small-scale model, namely a core cartilaginous tissue surrounded…”

Engineering cartilage or endochondral bone: A comparison of different naturally derived hydrogels

“…Alternatively, or perhaps in conjunction, inflammatory cytokines may be leveraged to direct more efficient resorption of a large cartilaginous template [51]. Hydrogels for endochondral applications may also benefit from the incorporation of channeled arrays, in order to provide additional conduits for vascularization [52].…”

Endochondral Ossification for Enhancing Bone Regeneration: Converging Native Extracellular Matrix Biomaterials and Developmental Engineering In Vivo

“…27,43,57,58,[61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] While cartilage tissue engineering strategies have focused on inducing and maintaining chondrogenic phenotypes, the induction and modulation of cartilage hypertrophy is critical to the progression of EC ossification in bone regeneration designs. 9,33,34,[37][38][39][40][41][42][43]72,[77][78][79][80][81][82][83][84][85] The key transcription factor involved in initial chondrogenesis is SOX9, whereas the primary hypertrophy associated factors are runtrelated transcription factor 2 (Runx2) and myocyte enhancer factor 2C (MEF2C). 33,34,41,78 In this critical maturation stage of EC ossification, chondrocytes experience a large increase in volume (*5-to 10-fold), and downstream proteins activated by Runx2 and MEF2C transcription factors begin to remodel the surrounding ECM.…”