Selective joint denervation promotes knee osteoarthritis in the aging rat

Abstract

Osteoarthritis is the most common joint disorder with aging, but its cause is unknown. Mice lose joint afferents with aging, and this loss precedes development of osteoarthritis. We hypothesized a loss of joint afferents is involved in the pathogenesis of osteoarthritis.To test this hypothesis, we denervated knee joints of 16 rats at age 2 months, by intra-articular injection o f an immunotoxin. The imrnunotoxin killed neurons after retrograde axonal transport to the cell body. At 16 or 24 months follow-up, each joint was histologically assessed and assigned an osteoarthritis score.At follow-up, the number of joint afferents had spontaneously decreased by 42% in control knees and 69%~ in denervated knees. We found that control knees developed osteoarthritic changes with aging. However, denervated knees had far more severe changes, as evidenced by a 54% higher average osteoarthritis score than control knees ( P = 0.0016, both groups 16 knees).These results suggest a loss of afferents predisposes a joint to osteoarthritis. We propose the spontaneous loss o f neurons with aging may be a normal developmental process. To explain the mechanism causing osteoarthritis, we suggest denervation permits aberrant joint loading, either by disturbing neuromuscular joint control, or by inducing joint laxity after neurogenic loss of tissue homeostasis.

Ultrastructure and Innervation of Thumb Carpometacarpal Ligaments in Surgical Patients With Osteoarthritis

“…(3) Finally, is there a correlation between age and mechanoreceptor density? This has been reported in the literature in other joints [22,[36][37][38]. If a similar correlation is found, it may provide insight into the effect of age and severity progression of OA.…”

“…Other studies have suggested an age-related decrease of mechanoreceptors and consequently impaired proprioceptive traits [23,40,44]. Previous studies have also established a correlation between age and mechanoreceptor density [22,[36][37][38]. To date, underlying pathophysiological mechanisms of age-related changes of proprioception have not been fully delineated.…”

“…Consequently, neurosensory and neuromuscular impairment such as inadequate reflex control of periarticular muscles, impaired ligament function, or disturbed innervation may contribute to osteoarthritis (OA) [27,34,39]. Evidence in human and animal models [22,[36][37][38] supports the notion that joint denervation may cause an increase in cartilage degeneration, impairment of joint reflexes, and later onset or aggravation of OA. During the process of aging, there is a natural denervation process [37]; this may also contribute to an increasing prevalence of OA with age [22].…”

Morphologic changes in the vastus medialis muscle in patients with osteoarthritis of the knee

“…It is unlikely that neurogenic muscular atrophy is directly due to OA of the knee, since there are no reports in the literature of structural changes of the peripheral nerves as direct consequence of OA. It does seem conceivable, however, that denervation or reinnervation processes had already started before or soon after the initial clinical manifestation of OA, as evidenced by findings reported by Salo et al (41). In their study, experimentally induced loss of joint afferents in rats led on average to a 54% higher score of histologic severity of OA compared with control knees.…”

Neuronal pathways in tendon healing and tendinopathy - update

“…However, considerable more investigation is needed to provide clarity with regard to the dynamic aspects of their role(s), and how neural elements are modulated by genetics, aging, and sex and co-morbidities. Some of this complexity likely serves fundamental roles in repair and restoration of function, but it is clear also from the work of Salo et al (33,34,198) that innervation of normal joint tissues can decline with age in both rats and mice, and thus elevate risk for degenerative joint disease. Whether similar changes occur in tendons and ligaments throughout the body during aging and following events such as menopause, remains to be delineated.…”