Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis

We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA

Zoledronic Acid Implant Coating Results in Local Medullary Bone Growth

Osteoarthritis (OA) can necessitate surgical interventions to restore the function of the joint in severe cases. Joint replacement surgery is one of the procedures implemented to replace the damaged joint with prosthetic implants in severe cases of OA. However, after successful implantation, a fraction of OA patients still require revision surgery due to aseptic prosthetic loosening. Insufficient osseointegration is one of the factors that contribute to such loosening of the bone implant, which is commonly made from titanium-based materials. Zoledronic acid (ZA), a potent bisphosphonate agent, has been previously shown to enhance osseointegration of titanium implants. Herein, we fabricated ZA/Ca composites using a reverse microemulsion method and coated them with 1,2-dioleoyl-sn-glycero-3-phosphate monosodium salt (DOPA) to form ZA/Ca/DOPA composites. Titanium alloy screws were subsequently dip-coated with a suspension of the ZA/Ca/DOPA composites and poly(lactic-co-glycolic) acid (PLGA) in chloroform to yield Za/PLGA-coated screws. The coated screws exhibited a biphasic in vitro release profile with an initial burst release within 48 h, followed by a sustained release over 1 month. To assess their performance in vivo, the Za/PLGA screws were then implanted into the tibiae of Sprague–Dawley rats. After 8 weeks, microCT imaging showed new bone growth along the medullary cavity around the implant site, supporting the local release of ZA to enhance bone growth around the implant. Histological staining further confirmed the presence of new mineralized medullary bone growth resembling the cortical bone. Such local medullary growth represents an opportunity for future studies with alternative coating methods to fine-tune the local release of ZA from the coating and enhance complete osseointegration of the implant

Changes in Joint Contact Mechanics in a Large Quadrupedal Animal Model After Partial Meniscectomy and a Focal Cartilage Injury

Acute mechanical damage and the resulting joint contact abnormalities are central to the initiation and progression of posttraumatic osteoarthritis (PTOA). Study of PTOA is typically performed in vivo with replicate animals using artificially induced injury features. The goal of this work was to measure changes in a joint contact stress in the knee of a large quadruped after creation of a clinically realistic overload injury and a focal cartilage defect. Whole-joint overload was achieved by excising a 5-mm wedge of the anterior medial meniscus. Focal cartilage defects were created using a custom pneumatic impact gun specifically developed and mechanically characterized for this work. To evaluate the effect of these injuries on joint contact mechanics, Tekscan (Tekscan, Inc., South Boston, MA) measurements were obtained pre-operatively, postmeniscectomy, and postimpact (1.2-J) in a nonrandomized group of axially loaded cadaveric sheep knees. Postmeniscectomy, peak contact stress in the medial compartment is increased by 71% (p ¼ 0.03) and contact area is decreased by 35% (p ¼ 0.001); the center of pressure (CoP) shifted toward the cruciate ligaments in both the medial (p ¼ 0.004) and lateral (p ¼ 0.03) compartments. The creation of a cartilage defect did not significantly change any aspect of contact mechanics measured in the meniscectomized knee. This work characterizes the mechanical environment present in a quadrupedal animal knee joint after two methods to reproducibly induce joint injury features that lead to PTOA

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients