Uncarboxylated osteocalcin promotes osteogenesis and inhibits adipogenesis of mouse bone marrow‑derived mesenchymal stem cells via the PKA‑AMPK‑SIRT1 axis

Abstract

Osteoporosis is a bone disease characterized by reduced bone density, thin cortical bone and large gaps in the bone's honeycomb structure, which increases the risk of bone fragility. Uncarboxylated osteocalcin (unOC), a vitamin K-dependent bone protein, is known to regulate carbohydrate and energy metabolism. A previous study demonstrated that unOC promotes the differentiation of mouse bone marrow-derived mesenchymal stem cells (BMSCs) into osteoblasts, but inhibits their differentiation into adipocytes. However, the underlying mechanism remains unknown. The present study showed that unOC regulated the differentiation potential of BMSCs via protein kinase A (PKA)/AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signaling. SIRT1, a member of the sirtuin family with deacetylation functions, was upregulated by unOC in BMSCs. Transfection analyses with SIRT1 small interfering RNA indicated that the unOC-induced differentiation shift in BMSCs required SIRT1. Examination of SIRT1 downstream targets revealed that unOC regulated the acetylation levels of runt-related transcription factor (RUNX) 2 and peroxisome proliferator-activated receptor γ (PPARγ). Therefore, unOC inhibited adipogenic differentiation by PPARγ acetylation and promoted osteogenic differentiation by RUNX2 deacetylation. Moreover, phosphorylated PKA and AMPK protein levels increased after unOC treatment, which led to the upregulation of SIRT1. Western blot analysis with PKA and AMPK inhibitors indicated that the PKA-AMPK signaling pathway functioned upstream of SIRT1 and positively regulated SIRT1 expression. These findings led us to propose a model in which unOC regulated BMSC osteogenic differentiation through the PKA-AMPK-SIRT1 axis, giving evidence towards the therapeutic potential of unOC in osteoporosis treatment.

Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging

“…Mitochondrial dysfunction impairs the nutrient sensing, energy homeostasis, and differential abilities of BMSCs [ 137 ]. Key regulators include the adenine monophosphate–activated protein kinase (AMPK) pathway, the phosphoinositide 3-kinase (PI3K)–AKT pathway, FoxO transcription factors, peroxisome proliferator-activated receptor gamma coactivator 1 α(PGC-1α) and sirtuin (SIRT) [ 138 , 139 , 140 , 141 , 142 ]. SIRT1 and SIRT6 expression decrease in aged BMSCs [ 143 ].…”

Genetic interactions between Polycystin-1 and TAZ in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice

“…Interestingly, we found a similar increase in adipogenic markers in both PC1 and/or TAZ osteoblast conditional knockout mice. The increase of adipogenic markers could be theoretically explained by increased transdifferentiation of osteoblast precursors to adipocytes 43,44 , or effects of PC1 and TAZ in osteoblasts/osteocytes differentially releasing paracrine factors that modulate adipogenesis [45][46][47] , analogous to paracrine factors that regulate osteoclastogenesis. Regardless, our studies revealed that double Pkd1/TAZ Oc-cKO null mice had no differences in adipogenic markers relative to single Pkd1 Oc-cKO or TAZ Oc-cKO null mice, suggesting that polycystin-1 and TAZ regulate adipocyte differentiation through the common polycystins/TAZ pathway.…”

OSGIN2 regulates osteogenesis of jawbone BMSCs in osteoporotic rats

“…In addition, BSP also facilitates the osteogenic capacity of human BMSCs, which are the vital precursors of osteoblast for bone remodeling [ 24 ]. OCN has been investigated to modulate the balance of osteogenesis and adipogenesis of BMSCs, which is another crucial balance involved in bone metabolism [ 25 ]. Furthermore, OCN also alleviates osteogenic differentiation of BMSCs that is previously restricted under high glucose microenvironment [ 26 ].…”