Disruption of the murine Mop3 (also known as Bmal1 or Arntl) locus results in a loss of behavioral and molecular circadian rhythms. Although Mop3 null mice do not display anomalies in early development, they do display reduced activity as they age. In an effort to explain this decreased activity, we characterized the physiological and anatomical changes that occurred with age. We observed that Mop3 null mice display an increased mortality after 26 weeks of age and a phenotype best described as a progressive noninflammatory arthropathy. Although little pathology is observed prior to 11 weeks of age, by 35 weeks of age essentially all Mop3 null animals develop joint ankylosis due to flowing ossification of ligaments and tendons and almost complete immobilization of weight-bearing and nonweight-bearing joints. This pathology appears to explain the decreased activity of Mop3 null mice and suggests that MOP3 is an inhibitor of ligament and tendon ossification.
Cruciate disease is a common cause of chronic lameness in dogs. Midsubstance rupture of the cranial cruciate ligament (CCL) arises from progressive pathological failure, often under conditions of normal loading in adult dogs with CCL instability. A high risk of rupture is associated with inflammation of the synovium and adaptive or degenerative changes in the cells and matrix of the CCL. In contrast, CCL rupture in puppies is usually associated with traumatic injury and avulsion of the CCL from its sites of attachment.
Accumulation of fatigue microdamage in the MCP is important in the pathogenesis of FMCP. The underlying cause of this microdamage accumulation must be identified before treatment plans that will prevent further osteoarthritis of the elbow joint can be designed.
Synovitis is an early feature of the CrCLR arthropathy in dogs before development of joint instability clinically. Severity of synovitis is correlated with radiographic arthritis in joints with minimal to no clinically detectable CrCL damage.
The cellular and ECM changes in ruptured CCL that we have described appear to result from the cumulative effects of remodeling and adaptation to mechanical loading and microinjury. Treatment of early cruciate disease in dogs will need to inhibit or reverse these progressive changes to CCL tissue, which are directly associated with partial or complete structural failure of the CCL under conditions of normal activity.
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