Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial

Abstract

The majority of skeletal elements develop via endochondral ossification. This process starts with formation of mesenchymal cell condensations at prescribed sites and times in the early embryo and is followed by chondrogenesis, growth plate cartilage maturation and hypertrophy, and replacement of cartilage with bone and marrow. This complex stepwise process is reactivated and recapitulated in physiologic conditions such as fracture repair, but can occur extraskeletally in pathologies including heterotopic ossification (HO), Ossification of the Posterior Longitudinal Ligament (OPLL) and Hereditary Multiple Exostoses (HME). One form of HO is common and is triggered by trauma, invasive surgeries or burns and is thus particularly common amongst severely wounded soldiers. There is also a congenital and very severe form of HO that occurs in children with Fibrodysplasia Ossificans Progressiva (FOP) and is driven by activating mutations in ACVR1 encoding the type I bone morphogenetic protein (BMP) receptor ALK2. Current treatments for acquired HO, including NSAIDs and local irradiation, are not always effective and can have side effects, and there is no effective treatment for HO in FOP. This review article describes the research path we took several years ago to develop a new and effective treatment for both congenital and acquired forms of HO and specifically, the testing of synthetic retinoid agonists to block the initial and critical chondrogenic step leading to HO onset and progression. We summarize studies with mouse models of injury-induced and congenital HO demonstrating the effectiveness and mode of action of the retinoid agonists, including Palovarotene. Our studies have provided the rationale for, directly led to, an ongoing phase 2 FDA clinical trial to test efficacy and safety of Palovarotene in FOP. Top-line results released a few months ago by the pharmaceutical sponsor Clementia are very encouraging. Given shared developmental pathways amongst pathologies of extraskeletal tissue formation, Palovarotene may also be effective in HME as preliminary in vitro data suggest.

Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva

“…Retinoid signalling plays a critical biological role in many tissues and organ systems and is essential for chondrogenesis and the proper formation of the skeleton . Retinoic acid signalling is mediated through nuclear hormone receptors known as retinoic acid receptors (RAR) which act as key regulators of gene transcription.…”

“…Retinoic acid signalling is mediated through nuclear hormone receptors known as retinoic acid receptors (RAR) which act as key regulators of gene transcription. There are three RARs (α, β and γ) that form heterodimers with retinoic X receptors and subsequently bind to retinoic acid response elements in the enhancer regions of target genes . In the presence of their endogenous ligand, all‐trans retinoic acid ( at RA), the RAR–retinoic X receptor heterodimer acts as a transcriptional activator.…”

“…In the presence of their endogenous ligand, all‐trans retinoic acid ( at RA), the RAR–retinoic X receptor heterodimer acts as a transcriptional activator. However, in its un‐bound form, this receptor complex acts as a transcriptional repressor . The relationship between retinoid signalling and chondrogenesis is antagonistic: several elegant studies have shown that skeletal precursor cells treated with at RA, and with subsequent activation of retinoid signalling, have repressed chondrogenesis and cartilage formation .…”

“…The mice treated with NRX195183 showed significantly less heterotopic ossification compared to the nontreated control mice. Furthermore, they had lower expression of chondrogenic genes, including Sox9, collagen XI and X, and Runx2 . However, high doses of the agonist were required to achieve this result.…”

Expression and Role of IL-1β Signaling in Chondrocytes Associated with Retinoid Signaling during Fracture Healing

“…Retinoic acid (RA), the main active metabolite of retinol, is one of the key regulators of skeletal patterning during embryogenesis, and it regulates cartilage and bone development and growth [7]. RA is an important regulator of differentiation and cell proliferation in skeletal development, and retinoic acid receptor gamma (RARγ) has been demonstrated to be expressed specifically in growth plates from the chondrocyte proliferation zone to the hypertrophy zone [8]. Retinoids exert their effects by modulations of gene expression by two distinct classes of nuclear receptors, i.e., the retinoic acid receptors (RARα, -β, and -γ) and the retinoid X receptors (RXRα, -β, and -γ).…”