Background/Purpose: Tissue-intrinsic circadian molecular clocks control many physiological processes. The function of these clocks in cells of the musculoskeletal system and their contribution to disease is poorly understood however. Here, we investigated the peripheral joint phenotype in mice genetically deficient for the core circadian molecular clock regulator Brain and muscle Arntl-like 1 (Bmal1).

Methods: We generated mice with conditional deletion of Bmal1 in mesenchymal cells of the limbs by crossing Bmal1^fl/fl and Prx1-cre mice. Forepaws and hindfeet of Bmal1^fl/fl and Bmal1^fl/fl.Prx1-cre mice were analyzed by histology and micro-computed tomography at 4, 8, and 12 weeks of age. Germline Bmal^-/- mice were analyzed in parallel. Gene expression in the Achilles tendon was analyzed by real-time qPCR. 

Results: As previously described in Bmal1^-/- germline knockout mice, Bmal1^fl/fl.Prx1-cre mice develop spontaneous Achilles tendon ossification. In addition, both Bmal1^-/- and Bmal1^fl/fl.Prx1-cre mice develop an osteoproliferative arthropathy in their forepaws, most prominently affecting the metacarpophalangeal and proximal interphalangeal joints, with radiographic similarity to the osteophytes seen in human hand osteoarthritis. Both the Achilles tendon and forepaw phenotypes are 100% penetrant by 8 weeks of age. Gene expression analysis of mRNA isolated from the Achilles tendon of Bmal1^fl/fl.Prx1-cre mice demonstrated (1) a marked reduction in Bmal1 expression and (2) loss of the cyclic expression pattern of core clock genes (Clock, Nr1d1), indicating deregulation of the circadian molecular clock. Longitudinal gene expression analysis revealed up-regulation of genes involved in bone formation (Alpl, Ocn, Osx) in the Achilles tendon. Furthermore, we found induction of canonical target genes of Hedgehog signaling (Ptch1, Gli1) but not of Bone morphogenetic protein (BPM) or Wnt signaling pathways.

Conclusion: Mice with either global or mesenchymal cell-specific deletion of Bmal1 develop Achilles tendon ossification and a forepaw arthropathy with marked radiographic similarity to hand osteoarthritis. Disruption of circadian rhythms in peripheral tissues, such as tendons and joints, may contribute to degenerative conditions of the musculoskeletal system.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disruption-of-the-molecular-clock-in-mesenchymal-cells-causes-an-osteoarthritis-like-disease-in-mice/