Loss of lysyl hydroxylase 2 activates CRP-mediated cancer invasion through MEK/ERK/MMP9 signaling in the bone-microenvironment

Lysyl hydroxylase 2 (LH2), encoded by procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 ( Plod2 ) gene, plays critical roles in collagen cross-linking and bone matrix organization. Recent studies have also shown that aberrant LH2 expression is promotes tumor progression, but its specific role in modulating cancer behavior within the bone-microenvironment remains unclear. Given the clinical importance of bone metastasis and the involvement of inflammatory mediators in tumor-stromal interactions, understanding the LH2 function in bone-tumor dynamics is of particular interest. Here, we used bone-specific LH2 conditional knockout (bsLH2-cKO) mice to investigate the impact of LH2 deficiency on cancer progression in bone by proteomic analysis and bone invasion models. Protein expression profiling revealed that C-reactive protein (CRP) was markedly upregulated in bone marrow stromal cells isolated from bsLH2-cKO femurs. Our in vitro and in vivo analyses demonstrated that CRP significantly enhanced cancer proliferation and exacerbated bone destruction in bsLH2-cKO mice following tumor cell injection. Pathway analysis further indicated that CRP induced by LH2 deficiency promoted overexpression of matrix metalloproteinase-9 through activation of the MEK/ERK signaling pathway. These findings identify LH2 as a critical regulator of CRP-mediated cancer progression in the bone-microenvironment, suggesting that targeting the LH2-CRP axis may represent a promising therapeutic strategy for bone-invasive cancers.