{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSP7 – also known as Osterix – is a bone‐specific zinc finger transcription factor that serves as a master regulator of osteoblast differentiation and bone formation. Its expression is induced by osteogenic signals such as BMP‐2 and is almost exclusively restricted to skeletal cells, as demonstrated by its bone‐selective expression and its genetic association with bone mineral density. Studies using human and murine mesenchymal progenitors, osteoblast‐derived cell lines, and even adipose‑derived stem cells have shown that SP7 is essential for promoting the expression of key osteoblast markers and the synthesis of extracellular matrix proteins, while its absence results in defective bone formation and osteoblast maturation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSP7 function is exquisitely regulated at multiple levels. At the post‑transcriptional stage, several microRNAs – including miR‑637, miR‑93, and miR‑96 – target SP7 messenger RNA to fine‑tune osteogenic differentiation. In addition, its protein activity and stability are modulated by intracellular signaling pathways; for example, Akt and Erk1/2 both enhance SP7 stability and transcriptional potency, while CaMKII also interacts with SP7 to potentiate its activity. Moreover, post‑translational modifications—including ubiquitination and acetylation (mediated by CBP and counteracted by HDAC4)—further affect SP7 stability and function. Negative regulators such as p53 can bind SP7, thereby inhibiting its DNA binding and impairing its transcriptional activation of osteogenic targets."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "15"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its regulation, SP7 acts in a cooperative and context‑dependent manner to drive osteogenesis. It synergizes with other transcription factors such as Runx2 to coordinately activate osteoblast‑specific genes—including those encoding bone sialoprotein, osteocalcin, and collagen—as well as regulators of matrix remodeling like MMP13. SP7 also plays a role in maintaining bone homeostasis by regulating sclerostin expression and is critical for later stages of osteoblast maturation; for instance, its activity is required for proper osteocyte dendrite formation and connectivity. In response to mechanical stimuli—observed in periodontal ligament cells and ligament flavum cells—SP7 is upregulated to mediate stress‐induced osteogenic differentiation. Moreover, noncoding RNAs such as MALAT1, acting via microRNA sponging, have been shown to modulate SP7 expression, further emphasizing its central role in both physiological and pathological bone formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "23"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stan Gronthos, Shaoqiong Chen, Cun-Yu Wang, et al. 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