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Background: Supination-adduction (SAD) type II ankle fractures can have medial tibial plafond and talar body impaction. Factors associated with the development of posttraumatic arthritis can be intrinsic to the injury pattern or mitigated by the surgeon. We hypothesize that plafond malreducton and talar body impaction is associated with early posttraumatic arthrosis. Methods: A retrospective cohort of skeletally mature patients with SAD ankle fractures at 2 level 1 academic trauma centers who underwent operative fixation were identified. Patients with a minimum of 1-year follow-up were included. The presence of articular impaction identified on CT scan was recorded and the quality of reduction on final intraoperative radiographs was assessed. The primary outcome was radiographic ankle arthrosis (Kellgren-Lawrence 3 or 4), and postoperative complications were documented. Results: A total of 175 SAD ankle fractures were identified during a 10-year period; 79 patients with 1-year follow-up met inclusion criteria. The majority of injuries resulted from a high-energy mechanism. Articular impaction was present in 73% of injuries, and 23% of all patients had radiographic arthrosis (Kellgren-Lawrence 3 or 4) at final follow-up. Articular malreduction, defined by either a gap or step >2 mm, was significantly associated with development of arthrosis. Early treatment failure, infection, and nonunion was rare in this series. Conclusion: Malreduction of articular impaction in SAD ankle fractures is associated with early posttraumatic arthrosis. Recognition and anatomic restoration with stable fixation of articular impaction appears to mitigate risk of posttraumatic arthrosis. Investigations correlating postoperative and long-term radiographic findings to patient-reported outcomes after operative treatment of SAD ankle fractures are warranted. Level of Evidence: Level IV, retrospective case series.

Systemic sclerosis (SSc) is a complex human disorder characterized by progressive skin fibrosis. To better understand the molecular basis of dermal fibrosis in SSc, we analyzed microarray gene expression in skin of the Tight-skin (Tsk) mouse, an animal model where skin fibrosis is caused by an in-frame duplication in fibrillin-1 (Fbn-1). Tsk skin showed increased mRNA levels of several genes involved in Wnt signaling, including Wnt2, Wnt9a, Wnt10b and Wnt11; Dapper homolog antagonist of beta-catenin (DACT1) and DACT2; Wnt-induced secreted protein 2; and secreted frizzled-related protein (SFRP)2 and SFRP4. RNase protection and northern blot confirmed microarray results. Furthermore, Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin. Further analysis showed that SFRP4 expression is specifically increased in tissues expressing Tsk-Fbn-1, such as skeletal muscle and skin. The increase in SFRP4 mRNA in Tsk skin started 2 weeks after birth, following the increase in Wnt2 mRNA that occurred at birth. This suggests that SFRP4 may modulate Wnt functions in Tsk skin fibrosis. Lesional skin from SSc patients also showed large increases in SFRP4 mRNA and protein levels in the deep dermis compared to healthy skin, suggesting that the Wnt pathway might regulate skin fibrosis in SSc.

The hypoxia-inducible factor-1α (HIF-1α) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1α pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1α activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1 α in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro . One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1α pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing.

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time- course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. Introduction: Since FDA approval of PTH (PTH(1-34); Forteo) as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. Materials and Methods: Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 g/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. Results: Quantitative CT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to osteogenesis over the course of the repair process. In addition, chondrocyte hypertrophy occurred earlier in the PTH-treated callus tissues. Analysis of the expression of potential mediators of PTH actions showed that PTH treatment significantly induced the expression of Wnts 4, 5a, 5b, and 10b and increased levels of unphosphorylated, nuclear localized -catenin protein, a central feature of canonical Wnt signaling. Conclusions: These results showed that the PTH-mediated enhancement of fracture repair is primarily asso- ciated with an amplification of chondrocyte recruitment and maturation in the early fracture callus. Associated with these cellular effects, we observed an increase in canonical Wnt signaling supporting the conclusion that PTH effects on bone repair are mediated at least in part through the activation of Wnt-signaling pathways. J Bone Miner Res 2007;22:1903-1912. Published online on August 6, 2007; doi: 10.1359/JBMR.070724

Introduction: Distraction osteogenesis (DO) is characterized by the induction of highly vascularized new bone formation through an intramembranous process largely devoid of the formation of cartilage. Materials and Methods: To test the hypothesis that DO is strictly dependent on vascualrization, we inhibited vascular endothelial growth factor (VEGF) activity by antibody blockade of both receptors VEGFR1 (Flt-1) and VEGFR2 (Flk-1) or only VEGFR2 (Flk-1) in a previously developed murine tibia DO model. During normal DO, VEGFR1 (Flt-1), VEGFR2 (Flk-1), VEGFR3 (Flt4) and all four VEGF ligand (A, B, C, and D) mRNAs are induced. Results: The expression of mRNA for the receptors generally paralleled those of the ligands during the period of active distraction. Bone formation, as assessed by μCT, showed a significant decrease with the double antibody treatment and a smaller decrease with single antibody treatment. Vessel volume, number, and connectivity showed progressive and significant inhibition in all of these of parameters between the single and double antibody blockade. Molecular analysis showed significant inhibition in skeletal cell development with the single and double antibody blockade of both VEGFR1 and 2. Interestingly, the single antibody treatment led to selective early development of chondrogenesis, whereas the double antibody treatment led to a failure of both osteogenesis and chondrogenesis. Conclusions: Both VEGFR1 and VEGFR2 are functionally essential in blood vessel and bone formation during DO and are needed to promote osteogenic over chondrogenic lineage progression.

Ontogenetic development is initiated at the time of fertilization and terminates with the differentiation, growth, and maturation of specialized tissues and organs. These developmental processes are characterized by molecular specialization that accompanies cellular differentiation and tissue morphogenesis. Most developmental processes terminate after birth or when animals reach sexual maturity, but some morphogenetic processes are reinitiated in response to injury in specific tissues. One such regenerative process is the repair of skeletal fractures and bone tissue after surgery, a process that recapitulates specific aspects of the initial developmental processes in the course of healing [58, 209]. Several aspects of the postnatal tissue environment of fracture healing, however, are unique and differ from what occurs in embryological and postnatal development.