S U M M A R Y Cells in tendons are conventionally identified as elongated tenocytes and ovoid tenoblasts, but specific markers for these cells are not available. The roles and interplay of these cells in tendon growth, remodeling, and healing are not well established. Therefore, we proposed to characterize these cells with respect to cell turnover, extracellular matrix metabolism, and expression of growth factors. Here we examined 14 healthy human patellar tendon samples for the expression of various proteins in tenocytes and tenoblasts, which were identified as elongated tendon cells and ovoid tendon cells, respectively. Matrix metalloproteinase 1 (MMP1), procollagen type I (procol I), heat shock protein 47 (hsp47), bone morphogenetic protein 12 (BMP12), 13 (BMP13), and transforming growth factor ␤ 1 (TGF ␤ 1) were detected by immunohistochemistry (IHC). An image analysis of the IHC staining for proliferation cell nuclear antigen (PCNA) and apoptotic cells was performed to determine the proliferation index and the apoptosis index in elongated and ovoid tendon cells. The ovoid tendon cells expressed higher levels of procol I, hsp47, MMP1, BMP12, BMP13, and TGF ␤ 1 than the elongated tendon cells. Both the proliferation index and the apoptosis index of ovoid tendon cells were higher than those of the elongated tendon cells. The results suggested that ovoid tendon cells, conventionally recognized as tenoblasts, were more active in matrix remodeling. The expression of BMP 12, BMP13 and TGF ␤ 1 might be associated with the different cellular activities of tenoblasts and tenocytes.

Peri-tunnel bone loss after anterior cruciate ligament (ACL) reconstruction is commonly observed, both clinically and experimentally. We aimed to study the effect and mechanisms of different doses of alendronate in the reduction of peritunnel bone loss and promotion of graft-bone tunnel healing in ACL reconstruction. Eighty-four ACL-reconstructed rats were divided into 4 groups. Alendronate at different dosages, or saline, were injected subcutaneously weekly, for 2 or 6 weeks post-reconstruction, for vivaCT (computed tomography) imaging, biomechanical tests, histology and immunohistochemistry. Alendronate significantly increased bone mass and density of tissue inside bone tunnels except at the epiphyseal region of tibial tunnel. The femoral tunnel diameter decreased significantly in the mid-dose and highdose alendronate groups compared to that in the saline group at week 6. Alendronate significantly increased the peri-tunnel bone mass and density along all tunnel regions at week 6. Better graft-bone tunnel integration and intra-tunnel graft integrity were observed in the alendronate groups. The ultimate load was significantly higher in the mid-dose and high-dose alendronate groups at week 2, but not at week 6. There was a reduction in matrix metalloprotein (MMP)1, MMP13 and CD68-positive cells at the peri-tunnel region and graft-bone interface in the alendronate-treated group compared to the saline group. Alendronate reduced peritunnel bone resorption, increased mineralised tissue inside bone tunnel as well as histologically and biomechanically promoted graft-bone tunnel healing, probably by reducing the expression of MMP1, MMP13 and CD68-positive cells. Alendronate might be used for reducing peri-tunnel bone loss and promoting graft-bone tunnel healing at early stage post-ACL reconstruction.

Our understanding of the pathogenesis of "tendinopathy" is based on fragmented evidences like pieces of a jigsaw puzzle. We propose a "failed healing theory" to knit these fragments together, which can explain previous observations. We also propose that albeit "overuse injury" and other insidious "micro trauma" may well be primary triggers of the process, "tendinopathy" is not an "overuse injury" per se. The typical clinical, histological and biochemical presentation relates to a localized chronic pain condition which may lead to tendon rupture, the latter attributed to mechanical weakness. Characterization of pathological "tendinotic" tissues revealed coexistence of collagenolytic injuries and an active healing process, focal hypervascularity and tissue metaplasia. These observations suggest a failed healing process as response to a triggering injury. The pathogenesis of tendinopathy can be described as a three stage process: injury, failed healing and clinical presentation. It is likely that some of these "initial injuries" heal well and we speculate that predisposing intrinsic or extrinsic factors may be involved. The injury stage involves a progressive collagenolytic tendon injury. The failed healing stage mainly refers to prolonged activation and failed resolution of the normal healing process. Finally, the matrix disturbances, increased focal vascularity and abnormal cytokine profiles contribute to the clinical presentations of chronic tendon pain or rupture. With this integrative pathogenesis theory, we can relate the known manifestations of tendinopathy and point to the "missing links". This model may guide future research on tendinopathy, until we could ultimately decipher the complete pathogenesis process and provide better treatments.