Early osteoarthritis in heritable disorders of connective tissue: TGF-β-associated endophenotypes and subchondral bone remodeling

ABSTRACT. Early osteoarthritis (OA) developing in young individuals is increasingly recognized as one of the clinical manifestations of heritable disorders of connective tissue (HDCTs). In contrast to age-associated osteoarthritis, degenerative joint changes in HDCTs arise in the context of primary defects of the extracellular matrix, impaired mechanotransduction, and dysregulation of tissue-remodeling signaling pathways, particularly transforming growth factor-β (TGF-β). This review discusses the hypothesis of distinct endophenotypes of early OA in HDCTs, including a fibrotic endophenotype (predominantly associated with Marfan syndrome), and osteopenic and mixed endophenotypes, more commonly observed in hypermobility-related conditions such as the hypermobile type of Ehlers–Danlos syndrome. Particular emphasis is placed on the role of subchondral bone as an active pathogenic compartment and on TGF-β-mediated transdifferentiation of resident fibroblasts into α-smooth muscle actin (α-SMA)-positive myofibroblasts, which may promote the formation of a functionally compromised collagen matrix. Phenotypic stratification of early OA in HDCTs is considered a prerequisite for a personalized approach to diagnosis and management in this patient population.

For citation: Rudoy AS. Early osteoarthritis in heritable disorders of connective tissue: TGF-β-associated endophenotypes and subchondral bone remodeling. Therapy (Moscow). 2026;12(5S):104–115.
https://doi.org/10.18565/therapy.2026.5-s5.104-115

INTRODUCTION

Osteoarthritis (OA) has traditionally been considered a chronic degenerative joint disease associated with aging, mechanical overload, and metabolic factors [1]. However, OA often occurs in young adults without typical risk factors, suggesting that alternative pathogenetic mechanisms may be involved. One such clinical context is provided by heritable disorders of connective tissue (HDCTs), which encompass monogenic disorders such as Marfan syndrome (MFS) and the Ehlers–Danlos syndromes (EDS), as well as undifferentiated connective tissue dysplasia, which lacks well-defined diagnostic features [2].

These conditions are characterized by systemic extracellular matrix (ECM) defects affecting bone, cartilage, and ligaments, thereby predisposing patients to early musculoskeletal involvement. Clinically, these defects manifest as arthralgia, recurrent synovitis, joint instability, and premature degenerative changes that are often regarded as functional or nonspecific.

This review synthesizes current evidence on the pathogenesis and clinical endophenotypes of early OA in HDCTs, with particular emphasis on contemporary concepts of subchondral bone (SCB) remodeling and transforming growth factor beta (TGF-β) signaling.

HERITABLE DISORDERS OF CONNECTIVE TISSUE

In a simplified view, HDCTs comprise a heterogeneous group of monogenic disorders in which pathogenic variants affecting structural components of the ECM and/or regulators of ECM metabolism cause systemic abnormalities, primarily involving the musculoskeletal, cardiovascular, and ocular systems.

The classic HDCTs include MFS; the various EDS types, including hypermobile EDS (hEDS); other conditions associated with joint hypermobility, such as joint hypermobility syndrome (JHS; historically termed benign joint hypermobility syndrome), as defined by the Brighton criteria; Loeys–Dietz syndrome (LDS), which combines Marfan-like and EDS-like features; and disorders associated with osteopenia, such as osteogenesis imperfecta (OI).

Focusing on these classic forms is a deliberate simplification intended to facilitate a unified discussion of the clinical manifestations of connective tissue dysplasia. HDCTs encompass more than 250 monogenic syndromes and a broad spectrum of undifferentiated connective tissue dysplasia. They can be broadly divided into disorders caused by defects in structural ECM components and those caused by dysregulation of morphogenesis, including the TGF-β axis.

Many HDCTs result from pathogenic variants in genes encoding structural or metabolic ECM proteins. These include collagen α-chains; proteins involved in collagen biosynthesis, post-translational modification, and degradation; matrix metalloproteinases and their inhibitors; and noncollagenous ECM components. The latter group encompasses proteoglycanopathies, disorders of microfibrillar proteins – including fibrillinopathies, elastinopathies, and fibulinopathies – and glycoprotein disorders [3]. Another major group comprises genetic defects in regulatory systems governing connective tissue formation and remodeling, including pathogenic variants in genes encoding growth factors such as TGF-β and fibroblast growth factors (FGFs), their receptors and antagonists, and transcription factors. Together, these disorders define a common pathogenetic axis extending from the molecular architecture of the ECM to the signaling and transcriptional control of morphogenesis and tissue homeostasis [3].

Despite their substantial molecular and genetic heterogeneity, the clinical and pathogenetic core of HDCTs lies largely in abnormalities of bone, cartilage, and ligamentous tissue, a feature of particular relevance to the development of early OA. Most HDCTs are collagenopathies or disorders of other ECM proteins that impair the formation and remodeling of cartilage, SCB, ligaments, and tendons. Chondrodysplasias, skeletal dysmorphisms, hereditary arthropathies, osteoporosis, and OA are prominent within this spectrum and confer structural and biomechanical vulnerability on the joint from an early age.

Pathogenic variants in genes encoding proteoglycans, microfibrillar proteins, and morphogenetic regulators disrupt cartilage matrix organization, endochondral ossification, and the adaptive response of joint tissues to mechanical loading. By contrast, polymorphisms in genes encoding type I–III collagens primarily predispose to degenerative changes in bone and the ligaments.

Thus, despite the diversity of the underlying genetic syndromes, the osteoarticular phenotype represents their common pathogenetic denominator, and early OA provides one of the clearest clinical models of systemic ECM failure.

OSTEOARTHRITIS

OA is traditionally viewed as a disease of older adults; however, in HDCTs, it may present at a young age. Unlike autoimmune inflammatory arthritides, joint involvement in HDCTs is characterized predominantly by noninflammatory degenerative changes arising in the setting of congenital...

A.S. Rudoy