Mesenchymal MACF1 Facilitates SMAD7 Nuclear Translocation to Drive Bone Formation

Abstract

Microtubule actin crosslinking factor 1 (MACF1) is a large crosslinker that contributes to cell integrity and cell differentiation. Recent studies show that MACF1 is involved in multiple cellular functions such as neuron development and epidermal migration, and is the molecular basis for many degenerative diseases. MACF1 is highly abundant in bones, especially in mesenchymal stem cells; however, its regulatory role is still less understood in bone formation and degenerative bone diseases. In this study, we found MACF1 expression in mesenchymal stem cells (MSCs) of osteoporotic bone specimens was significantly lower. By conditional gene targeting to delete the mesenchymal Macf1 gene in mice, we observed in MSCs decreased osteogenic differentiation capability. During early stage bone development, the MACF1 conditional knockout (cKO) mice exhibit significant ossification retardation in skull and hindlimb, and by adulthood, mesenchymal loss of MACF1 attenuated bone mass, bone microarchitecture, and bone formation capability significantly. Further, we showed that MACF1 interacts directly with SMAD family member 7 (SMAD7) and facilitates SMAD7 nuclear translocation to initiate downstream osteogenic pathways. Hopefully these findings will expand the biological scope of the MACF1 gene, and provide an experimental basis for targeting MACF1 in degenerative bone diseases such as osteoporosis.

Silencing of miR-138-5p sensitizes bone anabolic action to mechanical stimuli

“…Our previous data show that MACF1 positively regulates osteoblast differentiation and bone formation by activating the Wnt/β-catenin or BMP signaling pathways 49 - 52 , which are also likely involved in miR-138 regulation of osteogenic differentiation 47 , 48 . In addition, MACF1, as a cytoskeleton crosslinker, is negatively correlated with age and also mechanoresponsive under different mechanical conditions 49 , 52 - 55 . We also found that the transfection of the Macf1 3'UTR repeated sequence showed effects similar to those of the miR-138-5p inhibitor.…”

Targeting long noncoding RNA PMIF facilitates osteoprogenitor cells migrating to bone formation surface to promote bone formation during aging

“…Microtubule actin crosslinking factor 1 (MACF1), a spectraplakin protein that interacts with the cytoskeleton, plays an important role in cell migration 10 - 13 . We previously found that Macf1 was significantly downregulated in aged osteoporotic patients 14 . In the current study, we identified a long non-coding RNA PMIF (postulated migration inhibitory factor, i.e.…”

microRNA‐148a‐3p in extracellular vesicles derived from bone marrow mesenchymal stem cells suppresses SMURF1 to prevent osteonecrosis of femoral head

“…Furthermore, down‐regulated Smad ubiquitination regulatory factor 1 (SMURF1) is found to promote the expression of SMAD7 in mesangial cells 12,13 . SMAD7 is promoted by the interaction between microtubule actin crosslinking factor 1 and SMAD7 to accelerate the osteogenesis 14 . Furthermore, up‐regulated SMAD7 is closely related to the proliferation of BMSCs 15 .…”