Clubfoot, medically termed congenital talipes equinovarus (CTEV), is a prevalent musculoskeletal birth defect, affecting approximately 0.3% of all live births. This serious congenital anomaly results from structural abnormalities in the foot and lower leg, leading to abnormal positioning of the ankle and foot joints. This review provides a comprehensive overview of the causative factors associated with CTEV and evaluates current therapeutic approaches. Although variations in genes encoding contractile proteins of skeletal myofibers have been proposed as contributors to the etiology of CTEV, no definitive candidate genes have been conclusively linked to increased risk. However, genes such as TBX4, PITX1, and members of the HOXA, HOXC, and HOXD clusters, as well as NAT2, have been implicated in the condition’s development, playing critical roles in limb development, muscle formation, and tissue differentiation. Also, Axin1 plays a key role in joint formation and skeletal development by inhibiting β-catenin-BMP signaling. It could significantly serve as a therapeutic target for fibular hemimelia and multiple synostoses syndrome. The exact mechanisms and the extent of their physical and genetic interactions remain subjects of ongoing research. Understanding the genetic determinants and cellular pathways involved in CTEV is crucial for unravelling the pathophysiology of this complex deformity.

Osteoarthritis (OA) is a chronic degenerative joint disease. Currently, OA is incurable. Abnormal activation of canonical Wnt/β-catenin or Indian hedgehog (Ihh) signaling could lead to OA development and progression. This study aimed to determine if targeting β-catenin and Ihh signaling could yield an effective therapeutic intervention for OA disease. CRISPR/CasRx is a new RNA interference tool that can precisely and efficiently cleave single-strand RNAs. In this study, we screened CRISPR-derived RNA (crRNA) targeting Ctnnb1 and Smo in vitro and selected two optimal crRNAs for each gene. CasRx-mediated Ctnnb1 and Smo knockdown showed high efficiency and specificity with no obvious off-target effects in vitro. We then performed intra-articular injection of selected crRNAs driven by the adeno-associated virus into an OA mouse model. Micro-CT, histological, and histomorphometric analyses were conducted to evaluate the efficacy of CasRx approach on OA treatment. We found that the knockdown of Ctnnb1 and Smo decelerated pathological damage in the keen joint of the experimental OA mouse model. Our findings suggest that CasRx-mediated Ctnnb1 and Smo knockdown could be a potential strategy for OA treatment.

Osteoarthritis (OA) is a debilitating chronic joint disease affecting large populations of patients, especially the elderly. The pathological mechanisms of OA are currently unknown. Multiple risk factors are involved in OA development. Among these risk factors, alterations of mechanical loading in the joint leading to changes in biological signaling pathways have been known as a key event in OA development. The importance of AMPK-β-catenin-Runx2 signaling in the initiation and progression of OA has been recognized in recent years. In this review, we discuss the recent progress in understanding the role of this signaling pathway and the underlying interaction mechanisms during OA development. We also discuss the drug development aiming to target this signaling pathway for OA treatment.

Numerous small-molecule amines (SMAs) play critical roles in maintaining bone homeostasis and promoting bone regeneration regardless of whether they are applied as drugs or biomaterials. On the one hand, SMAs promote bone formation or inhibit bone resorption through the regulation of key molecular signaling pathways in osteoblasts/osteoclasts; on the other hand, owing to their alkaline properties as well as their antioxidant and anti-inflammatory features, most SMAs create a favorable microenvironment for bone homeostasis. However, due to a lack of information on their structure/bioactivity and underlying mechanisms of action, certain SMAs cannot be developed into drugs or biomaterials for bone disease treatment. In this review, we thoroughly summarize the current understanding of SMA effects on bone homeostasis, including descriptions of their classifications, biochemical features, recent research advances in bone biology and related regulatory mechanisms in bone regeneration. In addition, we discuss the challenges and prospects of SMA translational research.

Spine degeneration is an aging-related disease, but its molecular mechanisms remain unknown, although elevated β-catenin signaling has been reported to be involved in intervertebral disc degeneration. Here, we determined the role of β-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit (FSU), which includes the intervertebral disc, vertebra and facet joint and is the smallest physiological motion unit of the spine. We showed that pain sensitivity in patients with spinal degeneration is highly correlated with β-catenin protein levels. We then generated a mouse model of spinal degeneration by transgenic expression of constitutively active β-catenin in Col2⁺ cells. We found that β-catenin-TCF7 activated the transcription of CCL2, a known critical factor in osteoarthritic pain. Using a lumbar spine instability model, we showed that a β-catenin inhibitor relieved low back pain. Our study indicates that β-catenin plays a critical role in maintaining spine tissue homeostasis, its abnormal upregulation leads to severe spinal degeneration, and its targeting could be an avenue to treat this condition.

Osteoarthritis (OA) is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body. The molecular mechanisms of OA are currently unknown. OA is a heterogeneous disease that affects the entire joint, and multiple tissues are altered during OA development. To better understand the pathological mechanisms of OA, new approaches, methods, and techniques need to be used to understand OA pathogenesis. In this review, we first focus on the epigenetic regulation of OA, with a particular focus on DNA methylation, histone modification, and microRNA regulation, followed by a summary of several key mediators in OA-associated pain. We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain, such as CRISPR, scRNA sequencing, and lineage tracing. Next, we discuss the timely updates concerning cell death regulation in OA pathology, including pyroptosis, ferroptosis, and autophagy, as well as their individual roles in OA and potential molecular targets in treating OA. Finally, our review highlights new directions on the role of the synovial lymphatic system in OA. An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.