Background/Purpose: Excessively osteoclasts (OCs) activation play an essential role in bone erosions in rheumatoid arthritis (RA). Thus, controlling OCs would be an effective strategy to prevent pathological bone resorption. OCs originate from the hematopoietic monocyte-macrophage lineage. We previously showed that MKL1 is high expressed in macrophages and is indispensable for TNFα induced proinflammatory transcription in macrophages. Here, we explored the effect of MKL1 on OCs differentiation and function and examined its role on bone resorption during inflammatory arthritis.

Methods: OCs differenation and function were assayed by TRAP staining and pit formation assay. Bone erosions in collagen induced arthritis mice (CIA) was analyzed by histopathology and MicroCT. RNA-seq was used to detect the potential mechanism that involved in OCs formation after conditional deletion of MKL1 in macrophages.

Results: The multinucleated osteoclast formation in vitro was impaired in bone marrow cells isolated from the KO mice compared with those from wild-type mice (WT). OCs related genes expression included TRAP and CTSK were significantly down-regulated in KO mice. Targeted ablation of MKL1 in macrophages resulted in decreased OCs numbers in bone marrow and increased bone mass in KO mice. In contrast, no effect on T cells, B cells and monocyte numbers in bone marrow.  Deletion of MKL1 mice showed the mild bone resorption after subcutaneously injecting of LPS on calvariae compared with WT mice. In a CIA model , KO mice exhibited the delayed arthritis onset, mild arthritis score, lower synovial inflammatory cell infiltration and decreased bone erosion, as compared with WT mice. RNA-seq indicated that OCs derived from mice with macrophage MKL1-deficient mice had an increased Rho kinase and IFN signaling pathway.

Conclusion: Our data suggested that MKL1 plays an important role in regulation osteoclast formation and bone erosions in CIA mice.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/conditional-deletion-of-mkl1-inhibits-osteoclast-formation-and-bone-erosions-in-collagen-induced-arthritis-mice/