P62/sequestosome 1 deficiency accelerates osteoclastogenesis in vitro and leads to Paget's disease-like bone phenotypes in mice.

ABSTRACT: The sequestosome 1 gene encodes the p62 protein and is the major genetic risk factor associated with Paget's disease of bone. In 2004, p62 was reported to up-regulate osteoclast differentiation by activating the transcription factors Nfatc1 and NF-?B. Here, we characterized the osteoclastogenic potential of murine p62-/--derived cells compared with WT cells. Our data confirmed previous findings indicating that p62 is induced during murine osteoclast differentiation. Surprisingly, an indispensable role for p62 in in vitro osteoclast differentiation was not reproducible because p62-deficient osteoclasts exhibited robust activation of Nfatc1, NF-?B, and osteoclast marker enzymes. Thus, we concluded that in vitro osteoclast differentiation is not negatively influenced by knocking out p62. On the contrary, our results revealed that p62 deficiency accelerates osteoclastogenesis. Differentiation potential, multinucleation status, and soluble receptor activator of NF-?B ligand (sRANKL) sensitivity were significantly elevated in p62-deficient, murine bone marrow-derived stem cells. Moreover, femur ultrastructures visualized by micro-computed tomography revealed pronounced accumulation of adipocytes and trabecular bone material in distal femora of obese p62-/- mice. Increased tartrate-resistant acid phosphatase activity, along with increased trabecular bone and accumulation of adipocytes, was confirmed in both paraffin-embedded decalcified and methyl methacrylate-embedded nondecalcified bones from p62-/- mice. Of note, Paget's disease-like osteolytic lesions and increased levels of the bone turnover markers CTX-I and PINP were also observed in the p62-/- mice. Our results indicate that p62 predominantly suppresses murine in vitro osteoclast differentiation and highlight previously undetected Paget's disease-like phenotypes in p62-/- mice in vivo.

SUBMITTER: Zach F 

PROVIDER: S-EPMC6005453 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature