Background

There are currently no effective treatments for skeletal muscle fibrosis. Myofibroblasts are the major cellular effectors of fibrosis but their origin in muscle is unknown. We report that PDGFRβ (platelet derived growth factor receptor beta) Cre inactivates genes in murine PDGFRβ+ cells and myofibroblasts in muscle with high efficiency. We used this system to delete the integrin αv subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs.

Scar tissue formation secondary to acute muscle injury, surgical wounding and compartment syndrome can result in significant functional impairment and predispose to further injury. The source of fibroblasts, and the molecular mechanisms driving their activation and persistence in skeletal muscle fibrosis are not known. We hypothesized that cells expressing PDGFRβ become fibroblasts in response to injury and that targeting αv integrins in these cells reduces skeletal muscle fibrosis.

We used double-fluorescent reporter mice to demonstrate that cells expressing PDGFRβ become activated myofibroblasts in response to cardiotoxin (CTX) induced skeletal muscle injury. Following injury, PDGFRβ+ cells moved from perivascular locations into the interstitium in a distribution characteristic of fibroblasts, and showed marked induction of fibroblastic genes including αSMA and collagen1 (all p<0.0001). To confirm that αv integrins present on PDGFRβ cells critically regulate skeletal muscle fibrosis we used Itgavflox/flox;PDGFRβ-Cre mice (transgenic mice in which αv integrins are ‘knocked-down’ in PDGFRβ+ cells). These mice were significantly protected from CTX induced fibrosis (p<0.01). To demonstrate potential clinical utility of targeting αv integrins, we used a small molecule inhibitor of αv integrins (CWHM12). Treatment with CWHM12 significantly reduced fibrosis when delivered from the time of injury (p<0.01) and when delivered after the fibrotic response had become established (p<0.01).

We have identified a core pathway regulating fibrosis in skeletal muscle. Pharmacologic inhibition of αv integrins has potential clinical utility in the treatment and prevention of skeletal muscle fibrosis.

Method: We reviewed the hospital notes of 45 patients who underwent a lumbar discectomy over a 30month period. The care pathway was divided into three components: Pre-Hospital Wait (time from GP referral to first outpatient appointment), Hospital Wait (first out-patient appointment to being listed for surgery) and the Waiting List period.

The patients were divided into three groups: those following a standard pathway (group I), patients referred with an MRI scan (group II) and emergency admissions to hospital (group III).

Results: The groups I, II and III comprised of 18, 12 and 7 patients respectively. The mean Pre-Hospital Wait in weeks was 16 (group I) and 14 (group II). The Hospital Wait was 12 (group I), 3 (group II) and 1 (group III). The Waiting List period was 26 (group I), 18 (group II) and 1 (group III). The difference in The Hospital Wait between groups I and II reached significance.

Discussion: The Waiting List Period is often blamed as the causa principale for a delay in treatment. This review shows that a considerable time is spent in the Hospital Wait period and draws attention to a recognised delay in the care pathway, which requires a multidisciplinary approach to reduce its effect.