Table 1.

Regulation of skeletal-related gene pathways and their effects on SSCs and skeletal maintenance.

Gene/Pathway	Regulation in aged cells	Effects on SSCs and the skeletal system
Sirtuin1	Downregulated	Histone deacetylation protein implicated in aging and a target for rejuvenation therapeutics, reactivation of Sirt1 improves osteogenic differentiation in aged SSCs [29].
CSF1	Upregulated	A key signaling cue for osteoclastogenesis from SSC-derived cell populations, increased CSF1 signaling corresponds with higher osteoclast activity, while inhibition promotes osteogenesis of SSCs [5,9,31].
BMP2	Downregulated	Diminished signaling of BMP2 with SSCs may be related to poor formation of bone and articular cartilage; differentiation can be induced through combinatorial treatment with BMP2 and sVEGFR (chondrogenesis) or CSF1 (osteogenesis) [19,20,30,48,49].
VEGF	Upregulated	Increased VEGF signaling contributes to formation of fibrocartilage; combinatorial treatment with BMP2 induces formation of articular cartilage by activated SSCs [19,20,30].
MMP13	Upregulated	Increased production of MMP13 is associated with formation of hypertrophic chondrocytes and fibrocartilage, disrupting homeostasis of articular cartilage and bone [30,46,47].
TGF-β	Downregulated	Diminished TGF-β signaling results in impaired osteoblast activity and decreased bone formation [31,33,46,47].
WNT	Downregulated	Diminished WNT signaling in aged SSCs may contribute to stem cell senescence and promote osteoclast activity [29,48,49].
NF-κB	Upregulated	Increased humoral circulation of NF-κB corresponds with chronic age-related inflammation and diminished osteogenic activity; inhibition of NF-κB in aged cells restores youthful phenotype [50–52].