Pharmacotherapies in Dupuytren Disease: Current and Novel Strategies.

Dupuytren disease is a benign, progressive fibroproliferative disorder of the hands. To date, only one pharmacotherapy (clostridial collagenase) has been approved for use in Dupuytren disease. There is a great need for additional nonsurgical methods that can be used to either avoid the risks of invasive treatments or help minimize recurrence rates following treatment. A number of nonsurgical modalities have been discussed in the past and continue to appear in discussions among hand surgeons, despite highly variable and often poor or no long-term clinical data. This article reviews many of the pharmacotherapies discussed in the treatment of Dupuytren disease and novel therapies used in inflammation and fibrosis that offer potential treatment options.

Blocking CCN2 Reduces Established Palmar Neuromuscular Fibrosis and Improves Function Following Repetitive Overuse Injury.

The matricellular protein cell communication factor 2/connective tissue growth factor (CCN2/CTGF) is critical to development of neuromuscular fibrosis. Here, we tested whether anti-CCN2 antibody treatment will reduce established forepaw fibro-degenerative changes and improve function in a rat model of overuse injury. Adult female rats performed a high repetition high force (HRHF) task for 18 weeks. Tissues were collected from one subset after 18 wks (HRHF-Untreated). Two subsets were provided 6 wks of rest with concurrent treatment with anti-CCN2 (HRHF-Rest/anti-CCN2) or IgG (HRHF-Rest/IgG). Results were compared to IgG-treated Controls. Forepaw muscle fibrosis, neural fibrosis and entheseal damage were increased in HRHF-Untreated rats, compared to Controls, and changes were ameliorated in HRHF-Rest/anti-CCN2 rats. Anti-CCN2 treatment also reduced phosphorylated-ß-catenin (pro-fibrotic protein) in muscles and distal bone/entheses complex, and increased CCN3 (anti-fibrotic) in the same tissues, compared to HRHF-Untreated rats. Grip strength declines and mechanical sensitivity observed in HRHF-Untreated improved with rest; grip strength improved further in HRHF-Rest/anti-CCN2. Grip strength declines correlated with muscle fibrosis, entheseal damage, extraneural fibrosis, and decreased nerve conduction velocity, while enhanced mechanical sensitivity (a pain-related behavior) correlated with extraneural fibrosis. These studies demonstrate that blocking CCN2 signaling reduces established forepaw neuromuscular fibrosis and entheseal damage, which improves forepaw function, following overuse injury.

Blocking CCN2 preferentially inhibits osteoclastogenesis induced by repetitive high force bone loading.

Purpose/Aim: We recently found that blocking CCN2 signaling using a monoclonal antibody (FG-3019) may be a novel therapeutic strategy for reducing overuse-induced tissue fibrosis. Since CCN2 plays roles in osteoclastogenesis, and persistent performance of a high repetition high force (HRHF) lever pulling task results in a loss in trabecular bone volume in the radius, we examined here whether blocking CCN2 signaling would reduce the early catabolic effects of performing a HRHF task for 3 weeks. Materials and Methods: Young adult, female, Sprague-Dawley rats were operantly shaped to learn to pull at high force levels, before performing the HRHF task for 3 weeks. HRHF task rats were then left untreated (HRHF Untreated), treated in task weeks 2 and 3 with a monoclonal antibody that antagonizes CCN2 (HRHF+FG-3019), or treated with an IgG (HRHF+IgG), while continuing to perform the task. Non-task control rats were left untreated. Results: In metaphyseal trabeculae of the distal radius, HRHF Untreated and HRHF-IgG rats showed increased osteoblast numbers and other indices of bone formation, compared to controls, yet decreased trabecular bone volume, increased osteoclast numbers, and increased serum CTX-1 (a serum biomarker of bone resorption). HRHF+FG-3019 rats also showed increased osteoblast numbers and bone formation, but in contrast to HRHF Untreated and HRHF-IgG rats, showed higher trabecular bone volume, and reduced osteoclast numbers and serum CTX-1 levels (and statistically similar to Control levels). Conclusions: HRHF loading increased bone formation in each task group, yet blocking CCN2 dampened trabecular bone catabolism by reducing osteoclast numbers and activity.

Versatility of the Medial Femoral Condyle Flap for Extremity Reconstruction and Identification of Risk Factors for Nonunion, Delayed Time to Union, and Complications.

BACKGROUND: The medial femoral condyle (MFC) flap has become a popular choice for treatment of small bony defects. We aim to describe outcomes after MFC flap treatment of upper and lower extremity osseous defects and test the null hypothesis that no factors influence risks for nonunion, increased time to union, and complications. METHODS: A retrospective chart review was performed on all patients undergoing MFC free vascularized bone flaps by the senior author between May 2010 and March 2016. Preoperative, intraoperative, and postoperative data were collected. RESULTS: We identified 29 patients for inclusion (22 upper and 7 lower extremity reconstructions) treated with the MFC flap for diagnoses including long bone nonunion, avascular necrosis (AVN), or AVN with nonunion. Mean postoperative follow-up was 56 weeks. The average patient was 38 years old (range = 17-61 years) and had undergone 1.5 previous failed surgeries. Union was achieved in 86% of patients at a mean of 15.8 weeks (83% at 17.9 weeks for the scaphoid). No patient with lunate AVN progressed. There were no intraoperative flap complications or bone flap loss, but 28% underwent additional unplanned surgical procedures. We identified previous surgery as a risk factor for delayed union but did not observe significant risk factors predictive of nonunion or complications requiring unplanned reoperation. CONCLUSIONS: Extremity reconstruction using the MFC corticocancellous flap results in a high rate of union yet minimal donor morbidity for a challenging patient cohort. Previous surgery was a risk factor for increased time to union.

Computed tomography image guidance for more accurate repair of anterior table frontal sinus fractures.

BACKGROUND: Anterior table frontal sinus fractures accompanied by nasofrontal duct injury require surgical correction. Extracranial approaches for anterior table osteotomies have traditionally used plain radiograph templates or a "cut-as-you-go" technique. We compared these methods with a newer technique utilizing computed tomography (CT)-guided imaging. METHODS: Data of patients with acute, traumatic anterior table frontal sinus fractures and nasofrontal duct injury between 2009 and 2013 were reviewed (n = 29). Treatment groups compared were as follows: (1) CT image guidance, (2) plain radiograph template, and (3) cut-as-you-go. Frontal sinus obliteration was performed in all cases. Demographics, operative times, length of stay, complications, and osteotomy accuracy were recorded. RESULTS: Similar demographics, concomitant injuries, operative times, and length of stay among groups were noted. No patients in the CT-guided group had perioperative complications including intraoperative injury of the dura, cerebrum, or orbital structures. In the plain radiograph template group, 25% of patients had inadvertent dural exposure, and 12.5% required take-back to the operating room for cranial bone graft donor site hematoma. In the cut-as-you-go group, 11% required hardware removal for exposure. There were no cases of cerebrospinal fluid leak, meningitis, or mucocele in any group (follow-up, 29.2 months). The CT image guidance group had the most accuracy of the osteotomies (95%) compared with plain radiograph template (85%) and the cut-as-you-go group (72.5%). CONCLUSIONS: A new technique using CT image guidance for traumatic frontal sinus fractures repair offers more accurate osteotomy and elevation of the anterior table without increased operative times or untoward sequelae.

The skeletal site-specific role of connective tissue growth factor in prenatal osteogenesis.

BACKGROUND: Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted. RESULTS: We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-ß-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype. CONCLUSIONS: We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation.

Metacarpal fractures.

Metacarpal fractures are common and can be functionally disabling. The majority are managed non-operatively. When surgical intervention is indicated, various methods of fixation are available with the utility of each being based on injury pattern, patient function and surgeon preference. Early mobilization, especially in case of open reduction and internal fixation, is a critical component of treatment to prevent stiffness and restore function. When possible, a fixation construct that can withstand the applied forces of early postoperative motion is chosen. We provide an updated description for diagnosis, treatment options and operative fixation for metacarpal fractures.

Let's Focus on the Fibrosis in Dupuytren Disease: Cell Communication Network Factor 2 as a Novel Target.

Dupuytren disease is a progressive, benign fibroproliferative disorder of the hands that can lead to debilitating hand contractures. Once symptomatic, treatment involves either surgical intervention, specifically fasciectomy or percutaneous needle aponeurotomy, or enzymatic degradation with clostridial collagenase. Currently, collagenase is the only pharmacotherapy that has been approved for the treatment of Dupuytren contracture. There is a need for a pharmacotherapeutic that can be administered to limit disease progression and prevent recurrence after treatment. Targeting the underlying fibrotic pathophysiology is critical. We propose a novel target to be considered in Dupuytren disease-cell communication network factor 2/connective tissue growth factor-an established mediator of musculoskeletal tissue fibrosis.

Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats.

We have an operant model of reaching and grasping in which detrimental bone remodeling is observed rather than beneficial adaptation when rats perform a high-repetition, high-force (HRHF) task long term. Here, adult female Sprague-Dawley rats performed an intense HRHF task for 18 weeks, which we have shown induces radial trabecular bone osteopenia. One cohort was euthanized at this point (to assay the bone changes post task; HRHF-Untreated). Two other cohorts were placed on 6 weeks of rest while being simultaneously treated with either an anti-CCN2 (FG-3019, 40 mg/kg body weight, ip; twice per week; HRHF-Rest/anti-CCN2), or a control IgG (HRHF-Rest/IgG), with the purpose of determining which might improve the trabecular bone decline. Results were compared with food-restricted control rats (FRC). MicroCT analysis of distal metaphysis of radii showed decreased trabecular bone volume fraction (BV/TV) and thickness in HRHF-Untreated rats compared with FRCs; responses improved with HRHF-Rest/anti-CCN2. Rest/IgG also improved trabecular thickness but not BV/TV. Histomorphometry showed that rest with either treatment improved osteoid volume and task-induced increases in osteoclasts. Only the HRHF-Rest/anti-CCN2 treatment improved osteoblast numbers, osteoid width, mineralization, and bone formation rate compared with HRHF-Untreated rats (as well as the latter three attributes compared with HRHF-Rest/IgG rats). Serum ELISA results were in support, showing increased osteocalcin and decreased CTX-1 in HRHF-Rest/anti-CCN2 rats compared with both HRHF-Untreated and HRHF-Rest/IgG rats. These results are highly encouraging for use of anti-CCN2 for therapeutic treatment of bone loss, such as that induced by chronic overuse. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The role of connective tissue growth factor (CTGF/CCN2) in skeletogenesis.

Connective tissue growth factor (CTGF) is a 38 kDa, cysteine rich, extracellular matrix protein composed of 4 domains or modules. CTGF has been shown to regulate a diverse array of cellular functions and has been implicated in more complex biological processes such as angiogenesis, chondrogenesis, and osteogenesis. A role for CTGF in the development and maintenance of skeletal tissues first came to light in studies demonstrating its expression in cartilage and bone cells, which was dramatically increased during skeletal repair or regeneration. The physiological significance of CTGF in skeletogenesis was confirmed in CTGF-null mice, which exhibited multiple skeletal dysmorphisms as a result of impaired growth plate chondrogenesis, angiogenesis, and bone formation/mineralization. Given the emerging importance of CTGF in osteogenesis and chondrogenesis, this review will focus on its expression in skeletal tissues, its effects on osteoblast and chondrocyte differentiation and function, and the skeletal implications of ablation or over-expression of CTGF in knockout or transgenic mouse models, respectively. In addition, this review will examine the role of integrin-mediated signaling and the regulation of CTGF expression as it relates to skeletogenesis. We will emphasize CTGF studies in bone or bone cells, and will identify opportunities for future investigations concerning CTGF and chondrogenesis/osteogenesis.

Development of Normal and Cleft Palate: A Central Role for Connective Tissue Growth Factor (CTGF)/CCN2.

Development of the palate is the result of an organized series of events that require exquisite spatial and temporal regulation at the cellular level. There are a myriad of growth factors, receptors and signaling pathways that have been shown to play an important role in growth, elevation and/or fusion of the palatal shelves. Altered expression or activation of a number of these factors, receptors and signaling pathways have been shown to cause cleft palate in humans or mice with varying degrees of penetrance. This review will focus on connective tissue growth factor (CTGF) or CCN2, which was recently shown to play an essential role in formation of the secondary palate. Specifically, the absence of CCN2 in KO mice results in defective cellular processes that contribute to failure of palatal shelf growth, elevation and/or fusion. CCN2 is unique in that it has been shown to interact with a number of other factors important for palate development, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), epidermal growth factor (EGF), Wnt proteins and transforming growth factor-ßs (TGF-ßs), thereby influencing their ability to bind to their receptors and mediate intracellular signaling. The role that these factors play in palate development and their specific interactions with CCN2 will also be reviewed. Future studies to elucidate the precise mechanisms of action for CCN2 and its interactions with other regulatory proteins during palatogenesis are expected to provide novel information with the potential for development of new pharmacologic or genetic treatment strategies for clinical intervention of cleft palate during development.

Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse.

We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term performance of a high-repetition, low-force (HRLF) reaching task in rats. We hypothesized that grip strength declines would correlate with inflammation, fibrosis and degradation in flexor digitorum muscles and tendons. Grip strength declined after training, and further in weeks 18 and 24, in reach limbs of HRLF rats. Flexor digitorum tissues of reach limbs showed low-grade increases in inflammatory cytokines: IL-1ß after training and in week 18, IL-1α in week 18, TNF-α and IL-6 after training and in week 24, and IL-10 in week 24, with greater increases in tendons than muscles. Similar cytokine increases were detected in serum with HRLF: IL-1α and IL-10 in week 18, and TNF-α and IL-6 in week 24. Grip strength correlated inversely with IL-6 in muscles, tendons and serum, and TNF-α in muscles and serum. Four fibrogenic proteins, TGFB1, CTGF, PDGFab and PDGFbb, and hydroxyproline, a marker of collagen synthesis, increased in serum in HRLF weeks 18 or 24, concomitant with epitendon thickening, increased muscle and tendon TGFB1 and CTGF. A collagenolytic gelatinase, MMP2, increased by week 18 in serum, tendons and muscles of HRLF rats. Grip strength correlated inversely with TGFB1 in muscles, tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and with MMP2 in tendons and serum. Thus, motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task performance, and increased fibrogenic and degradative proteins with prolonged task performance. Serum TNF-α, IL-6, TGFB1, CTGF and MMP2 may serve as serum biomarkers of work-related musculoskeletal disorders, although further studies in humans are needed.