Minimally invasive, sustained-release relaxin-2 microparticles reverse arthrofibrosis.

Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology-the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.

The Prognosis of Arthrofibroses: Prevalence, Clinical Shortcomings, and Future Prospects.

Fibrosis is the dysregulated biosynthesis of connective tissue that results from persistent infection, high serum cholesterol, surgery, trauma, or prolonged joint immobilization. As a disease that impacts connective tissue, it is prevalent across the body and disrupts normal extracellular and tissue organization. Ultimately, fibrosis impairs the tissue structural, mechanical, or biochemical function. This review describes the clinical landscape of joint fibrosis, that is, arthrofibrosis, including the risk factors and causes, as well as current clinical treatments and their shortcomings. Because treating arthrofibrosis remains an unmet clinical challenge, we present several animal models used for exploration of the physiopathology of arthrofibrosis and summarize their use for testing novel treatments. We then discuss therapeutics for the prevention or treatment of arthrofibrosis that are in preclinical development and in ongoing clinical trials. We conclude with recent findings from molecular biological studies of arthrofibroses that shed insight on future areas of research for improved treatments.

ZBTB7A governs estrogen receptor alpha expression in breast cancer.

ZBTB7A, a member of the POZ/BTB and Krüppel (POK) family of transcription factors, has been shown to have a context-dependent role in cancer development and progression. The role of ZBTB7A in estrogen receptor alpha (ERα)-positive breast cancer is largely unknown. Approximately 70% of breast cancers are classified as ERα-positive. ERα carries out the biological effects of estrogen and its expression level dictates response to endocrine therapies and prognosis for breast cancer patients. In this study, we find that ZBTB7A transcriptionally regulates ERα expression in ERα-positive breast cancer cell lines by binding to the ESR1 promoter leading to increased transcription of ERα. Inhibition of ZBTB7A in ERα-positive cells results in decreased estrogen responsiveness as demonstrated by diminished estrogen-response element-driven luciferase reporter activity, induction of estrogen target genes, and estrogen-stimulated growth. We also report that ERα potentiates ZBTB7A expression via a post-translational mechanism, suggesting the presence of a positive feedback loop between ZBTB7A and ERα, conferring sensitivity to estrogen in breast cancer. Clinically, we find that ZBTB7A and ERα are often co-expressed in breast cancers and that high ZBTB7A expression correlates with improved overall and relapse-free survival for breast cancer patients. Importantly, high ZBTB7A expression predicts a more favorable outcome for patients treated with endocrine therapies. Together, these findings demonstrate that ZBTB7A contributes to the transcriptional program maintaining ERα expression and potentially an endocrine therapy-responsive phenotype in breast cancer.

Epigenetic mechanisms behind cellular sensitivity to DNA damage.

Epigenetic regulation of gene expression in cells is a complex and dynamic process that remains incompletely understood. The architecture of the chromatin itself and its level of condensation can greatly impact the expression of genes as well as the sensitivity of the DNA to damage. The compact nature of heterochromatin typically results in gene silencing and resistance to DNA-damaging agents, while less compact euchromatin results in gene expression and increased sensitivity to injury. There are diverse ways in which the chromatin structure, and therefore the sensitivity of cells to damage, can be regulated, including post-translational modifications to both the histones within the chromatin and the DNA itself. These modifications are tightly controlled and correspond to various factors such as metabolism and cell cycle. When these processes are dysregulated, as in cancer cells, the chromatin structure is also altered, ultimately changing the gene expression profile as well as the susceptibility of cells to DNA-damaging agents commonly used for cancer treatments. Recent studies have shown that manipulating the various players involved in regulating post-translational modifications to chromatin and exploiting differences in metabolism may prove to be effective methods for modifying cancer and normal cell sensitivity to damaging agents. In this review we discuss various ways of regulating chromatin structure and how these changes can influence cellular sensitivity to damage as well as the implications of these relationships for improving the efficacy and safety of cancer treatments.