Blocking Ccn2 Reduces Established Losses in Bone Volume Induced by Prolonged Intense Loading by Increasing Osteoblast Activity and Trabecular Thickness

Spatial Transcriptomics in Bone Mechanomics: Exploring the Mechanoregulation of Fracture Healing in the Era of Spatial Omics

“…Known mechano-responsive genes were also present amongst the top-ranked genes including: Il11 (+17.5 fold) – a cytokine predominantly expressed in bone ( 30 , 31 ), Ccn2 (-3.7 fold) ( 21 , 32 ), Wnt7b (+3.4 fold) ( 33 , 34 ), Sost (+2.2 fold) – a Wnt-antagonist ( 35 , 36 ), Gja1 (+2.0 fold) – which encodes for the gap junction protein connexin 43 ( 37 ), Sfrp4 (-1.4 fold) – a Wnt-antagonist ( 38–40 ), and Cdkn1a (-0.7 fold) – a negative regulator of osteogenesis ( 41 , 42 ) (Figure 5[B][C]; Supplementary Table 2).…”

“…Osteoclast markers were less prominent in the results with expression of Ctsk and Acp5 not significantly different between Control and Loaded fracture sites and upregulation of genes associated with osteoclastogenesis (25,26) and osteoclast activity (26)(27)(28)(29): s100a8 (+2.3 fold), Ncf1 (+1.6 fold) and Mmp9 (+0.8 fold) (Figure 4 [H] -[J]; Figure 5[B][C]; Supplementary Table 2). Known mechano-responsive genes were also present amongst the top-ranked genes including: Il11 (+17.5 fold)a cytokine predominantly expressed in bone (30,31), Ccn2 (-3.7 fold) (21,32), Wnt7b (+3.4 fold) (33,34), Sost (+2.2 fold)a Wnt-antagonist (35,36), Gja1 (+2.0 fold)which encodes for the gap junction protein connexin 43 (37), Sfrp4 (-1.4 fold)a Wnt-antagonist (38)(39)(40), and Cdkn1a (-0.7 fold)a negative regulator of osteogenesis (41,42)…”

“…Coincident with this enhanced osteogenic response, Ccn2 (-3.7 fold)a master regulator of osteogenesis and chondrogenesis (21), Nbl1 (-2.1 fold)a BMP-antagonist (22), and Mgp (-1.4 fold)a potent mineralization inhibitor (23,24), were downregulated (Figure 5[B]; Supplementary Table 2). Osteoclast markers were less prominent in the results with expression of Ctsk and Acp5 not significantly different between Control and Loaded fracture sites and upregulation of genes associated with osteoclastogenesis (25,26) and osteoclast activity (26)(27)(28)(29): s100a8 (+2.3 fold), Ncf1 (+1.6 fold) and Mmp9 (+0.8 fold) (Figure 4 [H] -[J]; Figure 5[B][C]; Supplementary Table 2).…”

“…Coincident with this enhanced osteogenic response, Ccn2 (-3.7 fold)a master regulator of osteogenesis and chondrogenesis (21), Nbl1 (-2.1 fold)a BMP-antagonist (22), and Mgp (-1.4 fold)a potent mineralization inhibitor (23,24), were downregulated (fig 5 [B]; table S2).…”