Skeletal stem cells, a new direction for the treatment of bone and joint diseases

Abstract

Skeletal stem cells (SSCs) are tissue-specific stem cells characterized by their capacity for self-renewal and their position at the apex of the differentiation hierarchy. They can generate mature bone cell types essential for bone development, maintenance, and repair. Lineage tracing experiments have demonstrated that SSCs reside in the bone marrow, periosteum, and the resting zone of the growth plate. These findings not only enhance our understanding of bone growth and development mechanisms but also offer novel therapeutic strategies for conditions such as epiphyseal injuries, fractures, osteoarthritis (OA), and other orthopedic diseases. Recent advancements in biological scaffold technology, combined with 3D printing techniques, have facilitated bone tissue regeneration using bone stem cells. In OA, SSCs antagonize inflammatory factors, such as tumor necrosis factor-alpha and interleukin-1 beta, via paracrine secretion of insulin-like growth factor 1 and transforming growth factor-beta. Simultaneously, SSCs secrete matrix metalloproteinase inhibitors to maintain cartilage matrix homeostasis. In femoral head necrosis, SSCs promote angiogenesis by secreting vascular endothelial growth factor and optimize the repair microenvironment through immune regulation, such as by inhibiting the nuclear factor-kappa B pathway. Additionally, bone stem cells have shown promise in cartilage regeneration therapy, particularly in treating degenerative diseases like OA and articular cartilage damage, thereby improving joint function. This review summarizes the latest research progress on the role of skeletal stem cells in bone and joint injury regeneration and provides new insights into potential therapeutic approaches.

Key Words: Skeletal stem cells; Epiphyseal injuries; Osteoarthritis; Avascular necrosis of the femoral head; Cartilage injury

Core Tip: Skeletal stem cells (SSCs) are tissue-specific stem cells characterized by their capacity for self-renewal and their position at the apex of the differentiation hierarchy. They can generate mature bone cell types essential for bone development, maintenance, and repair. Lineage tracing experiments have demonstrated that SSCs reside in the bone marrow, periosteum, and the resting zone of the growth plate. These findings not only enhance our understanding of bone growth and development mechanisms but also offer novel therapeutic strategies for conditions such as epiphyseal injuries, fractures, osteoarthritis (OA), and other orthopedic diseases. Recent advancements in biological scaffold technology, combined with 3D printing techniques, have facilitated bone tissue regeneration using bone stem cells. Additionally, bone stem cells have shown promise in cartilage regeneration therapy, particularly in treating degenerative diseases like OA and articular cartilage damage, thereby improving joint function. This review summarizes the latest research progress on the role of SSC in bone and joint injury regeneration and provides new insights into potential therapeutic approaches.

INTRODUCTION

Bone and joint injuries are prevalent clinical conditions in orthopedics, with an increasing incidence observed in recent years[1-3]. Osteoarticular diseases encompass a range of conditions, including osteoarthritis (OA), rheumatoid arthritis, gouty arthritis, and others. The majority of these diseases are associated with varying degrees of cartilage damage. Epidemiological studies reveal distinct characteristics of cartilage injury, such as a significant gender disparity (higher incidence in females), a bimodal age distribution (predominantly affecting young and middle-aged individuals as well as the elderly), and anatomical specificity (primarily involving the knee and ankle joints). The rising incidence of cartilage injury is closely linked to population aging, obesity, and an increase in sports-related injuries[4-6]. Current treatment strategies for cartilage impairment can be categorized into nonoperative and surgical approaches[7-9]. For mild cartilage damage, such as superficial abrasions or wear, gradual repair and recovery can often be achieved through adequate rest, physical therapy (e.g., shortwave diathermy, electrical nerve stimulation), and pharmacological interventions (e.g., nonsteroidal anti-inflammatory drugs)[10]. These methods aim to alleviate inflammation, mitigate pain, and stimulate chondrocyte regeneration and repair[11]. However, complete recovery may prove challenging for more severe cartilage injuries, particularly those involving extensive cartilage defects or full-thickness cartilage lesions[12]. In such cases, surgical intervention becomes necessary, with options including cartilage repair surgery or cartilage transplantation. These procedures focus on restoring cartilage integrity and functionality, thereby reducing pain and enhancing joint performance[13,14]. Consequently, prompt treatment following articular cartilage injury is crucial for promoting effective cartilage repair and regeneration.

Stem cell therapy offers a novel therapeutic avenue for cartilage repair[15,16]. Stem cells, a unique population of undifferentiated cells characterized by their capacity for self-renewal, unlimited proliferation, and multidirectional differentiation, have been utilized in the treatment of various traumatic and degenerative bone and joint defects[17]. Skeletal stem cells (SSCs), also referred to as pre-chondrocytes, are adult stem cells located in the LaCroix ring of the metaphysis in the limbs of embryos or newborn animals. These cells exhibit the continuous proliferation and directed differentiation properties typical of stem cells[18]. In recent years, significant progress has been made in SSC research, particularly in the areas of bone regeneration, epiphyseal repair, and cartilage injury. In cartilage regeneration, SSCs secrete transforming growth factor-β1 to activate the downstream SMAD2/3 signaling pathway, thereby upregulating the expression of SOX9 and COL2A1, which in turn promotes chondrocyte proliferation and extracellular matrix synthesis[19,20]. Simultaneously, exosomes secreted by SSCs carrying miR-140-5p specifically target HDAC4 for inhibition, thereby enhancing chondrogenic differentiation capacity[21,22]. Moreover, SSCs inhibit the NF-κB pathway via interleukin (IL)-10 secretion, reducing the release of pro-inflammatory factors such as IL-1β and tumor necrosis factor-alpha (TNF-α), and thus alleviating the local inflammatory microenvironment[23,24]. In epiphyseal plate injury repair, SSCs activate Runx2 while inhibiting bone bridge formation through the BMP-2/Smad1/5 pathway. Additionally, they promote vascular endothelial cell migration and vascular remodeling via the VEGF-A/PI3K-Akt pathway[25-27]. Furthermore, their paracrine FGF2 regulates FGFR1 receptors, stimulating the orderly alignment of epiphyseal plate chondrocytes and preventing premature growth plate closure[28]. SSCs are tissue-specific stem cells that can self-renew and occupy the apex of their differentiation hierarchy, giving rise to mature bone cell types essential for bone growth, maintenance, and repair[29]. Research on SSCs not only enhances our understanding of bone growth and development mechanisms but also provides innovative therapeutic strategies for treating epiphyseal injuries[30]. This article reviews the application of SSCs in bone and joint injuries and lays the groundwork for their further clinical utilization.

SSCS FROM DIFFERENT SOURCES

Bone development, maintenance, and repair rely on the self-renewal and differentiation of SSC[31]. The existence of colony-forming SSCs has been confirmed, and progenitor cells for bone, cartilage, and stroma have been isolated for rigorous functional characterization[32]. Researchers have proposed that SSCs reside in the pericardium surrounding the epiphysis and exhibit stem cell characteristics (Figure 1). Furthermore, they identified fibroblast growth factor receptor 3 as a marker antigen for SSCs, providing a theoretical foundation for their isolation, culture, and identification[33]. SSCs primarily originate from the epiphyseal plate region and include mesenchymal stem cells (MSCs) and chondroprogenitors[34]. Recent lineage tracing experiments have demonstrated that SSCs are present in the bone marrow, periosteum, and resting zone of the growth plate[35]. The isolation of SSCs is mainly achieved through specific cell surface markers (CD45^-/TER119^-/Tie2^-/Thy1^-/6C3^-/CD105⁺/Alpha V⁺/CD200⁺)[36]. Some studies have further confirmed the presence of SSCs from the periosteum, growth plate, and bone marrow[37].

Figure 1 Skeletal stem cells from different sources. SSC: Skeletal stem cells.

SSCs from the periosteum

For the specific isolation of SSCS from broad mouse and human bone marrow stromal cell (BMSC) populations, cells were sorted based on the co-expression of the cell-surface markers CD146 (MCAM) and PDGFRα, while excluding cells positive for the hematopoietic lineage marker CD45 (PTPRC) and the endothelial lineage marker CD31 (PECAM1), bone marrow-derived SSC/stromal stem cells can be differentiated in vitro based on the positive cell surface markers CD146 and PDGFRα. Cells negative for the exclusion markers CD45 and CD31 were sorted out. In vivo, Cre-mediated DNA recombination techniques, such as gremlin 1 (Grem1)-CreER and Lepr-Cre transgenic mice, were utilized for identification[38]. Many markers associated with putative bone marrow SSCs, such as the BMP antagonist Grem1, have been identified in mice. Grem1+ cells are considered a type of SSC due to their multilineage differentiation capacity in vivo, their essential role in postnatal bone formation, and their long-term self-renewal ability. However, the intrinsic properties of these cells may be altered during isolation and in vitro culture, potentially due to sorting selection bias or non-physiological culture conditions, among them, Grem1+ cells are predominantly located in the metaphysis of long bones and differentiate into chondrocytes, osteoblasts, BMSC, and periosteal connective tissue cells shortly after birth. These cells play acritical role in bone formation and possess long-term self-renewal capacity. Lepr+ cells are primarily concentrated around blood vessels, generating bone marrow adipocytes in the early stages postnatally and gradually becoming the predominant source of osteoblasts with aging. A subset expressing Cxcl12 is also involved in bone injury repair, while certain Lepr+ BMSC subsets maintain an immature matrix phenotype to support hematopoiesis. The heterogeneity and functional diversity of these cells provide a crucial foundation for investigating bone development, repair, and associated diseases. However, it is important to consider the limitations of in vitro studies, as the characteristics of these cells may be altered under culture conditions[39].

SSCs from growth plate

The longitudinal growth mechanism of long bones primarily relies on the functional partitioning of the growth plate[40]. This dynamic process can be divided into several key stages: In the quiescent zone, slowly proliferating cells act as a reserve cell population that continuously generates chondroblasts; in the proliferative zone, these precursor cells form orderly columnar structures and rapidly divide to expand the growth plate; in the hypertrophic zone, mature chondrocytes undergo volume expansion and matrix remodeling before being eliminated by osteoclasts at the ossifying front, subsequently replaced by bone-marrow composite tissue[41,42]. Studies have shown that chondrocytes within the growth plate can transdifferentiate into osteoblasts[43]. Recent breakthroughs have been achieved regarding the spatiotemporal dynamics and functional heterogeneity of stem cells in the growth plate resting zone[44]. Lineage tracing using Col2a1-CreER and PTHrP-CreER revealed that chondrocytes undergo polyclonal-to-monoclonal evolution after birth, regulated by the MTORC1 signaling pathway[18]. PTHrP+ cells serve as the primary source for chondrogenesis and can differentiate into Col1a1+ osteoblasts and Cxcl12+stromal cells, supporting the hypothesis of trans differentiation through the hypertrophic cartilage stage.

However, "borderline chondrocytes" may transdifferentiate directly, indicating the potential existence of a bypass mechanism. Chan et al[37] isolated mouse and human growth plate cells capable of differentiating into multiple lineages using specific combinations of surface markers. Nevertheless, their functional homology to resting zone stem cells in vivo remains controversial and could be affected by culture-induced plasticity[37,45,46]. These findings offer a novel perspective for investigating bone development and regenerative medicine.

SSCs from bone marrow

Recent studies have demonstrated the existence of a distinct population of stem cells, referred to as periosteal stem cells (P-SSCs), within the inner periosteum, which possess multi-directional differentiation potential[47]. When cathepsin K (Ctsk) was co-employed with surface markers (CD45^-TER119^-CD31^-CD105^-CD200⁺), P-SSCs mediating intramembranous ossification were successfully labeled[48]. Whereas other SSC utilize an endochondral pathway to form bone from an initial cartilage template, periosteal skeletal progenitor cells (PSCs) generate bone through a direct intramembranous pathway, thereby establishing a cellular basis for the divergence between intramembranous and endochondral developmental pathways. PSCs sustain cortical bone structure via intramembranous ossification. Specific knockout of Osx, a pivotal osteogenic transcription factor in PSCs, leads to severe defects in periosteal mineralization. Notably, PSCs display remarkable plasticity following fracture: They not only expand significantly in number but also switch from intramembranous to endochondral osteogenesis, contributing approximately 50% of callus chondrocytes. This unique adaptability renders them a central driver of fracture repair[48-50]. Ctsk, traditionally regarded as an osteoclast marker, has been identified as labeling P-SSCs involved in intramembranous ossification when combined with specific cell-surface markers[41]. Ctsk-Cre-labeled CD45^-TER119^-CD31^-CD105^-CD200⁺ cells isolated from the mouse femoral periosteum exhibit self-renewal properties and reside at the apex of the differentiation hierarchy, generating all Ctsk-Cre-labeled skeletal cell types. These P-SSCs also express markers previously identified by Chan et al[37], suggesting that this surface immunophenotype may be shared among various stem cell populations. The absence of Osx transcription factors in Ctsk-Cre-labeled cells results in impaired fracture repair and defective cortical bone formation. Human periosteum contains a population of immunophenotype conserved PSCs (Lin^-CD90^-CD200⁺CD105^-) that exhibit multi-directional differentiation capacity and osteogenic potential in vivo. These findings not only elucidate the dual functions of PSCs in bone development and regeneration but also offer a theoretical foundation for the development of bone regeneration therapies focused on P-SSCs[51,52].

APPLICATION OF SSCS IN DIFFERENT DISEASES

SSC have demonstrated significant therapeutic value in regenerative medicine over recent years, attributed to their distinctive self-renewal capacity and multi-lineage differentiation potential. Research has highlighted the broad application potential of SSCs in bone and cartilage tissue repair, disease modeling, and tissue engineering. SSCs exhibit notable advantages in treating orthopedic diseases by differentiating into osteoblasts and chondrocytes to promote bone and joint repair[53-61]. Furthermore, through precise regulation of their differentiation process, SSCs can generate functional chondrocytes, thereby enhancing joint function[56]. From a molecular perspective, the pluripotency of SSCs is rooted in their unique signaling pathway regulatory network. By modulating the inflammatory microenvironment, SSCs can exert therapeutic effects in inflammatory bone diseases[30,57]. Additionally, SSCs have been shown to promote angiogenesis[58] and, under specific conditions, differentiate into myocytes and neural cells[59], properties that position them as promising therapeutic candidates for various degenerative diseases (Figure 2).

Figure 2 Application of skeletal stem cells in bone and joint injuries. SSC: Skeletal stem cells; IL: Interleukin; TNF: Tumor necrosis factor.

Application of SSCs in epiphyseal injuries

Epiphyseal injury refers to damage at multiple sites affecting the longitudinal growth mechanism of bone, including critical regions such as the epiphyseal plate, Ranvier's groove, articular cartilage, and metaphyseal area[60,61]. As the most prevalent type of fracture in children[62], epidemiological studies indicate that it constitutes approximately 18% to 18.5% of all pediatric bone injuries[2,63]. Such injuries can result in structural disruption and vascular compromise of the growth plate, leading to heterotopic ossification of cartilage tissue and ultimately forming bone bridge, which impairs growth plate function[64,65]. Without timely intervention, severe developmental abnormalities may occur, resulting in irreversible consequences such as overgrowth, deformity, or growth arrest[66]. Since SSC are localized within the epiphyseal growth plate region and possess multipotent differentiation potential[67], they demonstrate significant therapeutic value in repairing epiphyseal injuries.

Through the BMP/Wnt signaling pathway, SSCs can differentiate into osteoblasts, thereby promoting bone matrix secretion and mineralization[68-71]. Simultaneously, via the TGF-β pathway, they differentiate into functional chondrocytes to reconstruct the joint surface[72]. Notably, SSCs can restore the normal structure and function of the growth plate by modulating the Ihh/PTHrP signaling pathway[73,74]. Proangiogenic factors such as VEGF secreted by SSCs significantly enhance blood supply to the injured area, providing critical nutritional support for tissue repair[75-78]. Furthermore, anti-inflammatory factors like IL-10secreted by SSCs effectively suppress the NF-κB signaling pathway, regulating local inflammatory responses and thus facilitating the repair process[79-82].

SSCs promote tissue repair after epiphyseal injury through multiple mechanisms, including osteogenesis, chondrogenesis, angiogenesis, and inflammation regulation. Future research will aim to further refine the application strategies of SSCs to enhance both the safety and efficacy of their clinical use.

Application of SSC in OA

OA is a degenerative joint disease characterized by progressive degradation of articular cartilage, subchondral bone sclerosis, and synovial inflammation[83-85]. Global epidemiological data indicate that OA affects approximately 528 million individuals worldwide, with its prevalence continuing to rise due to aging populations and increasing obesity rates[86-88]. The hallmark pathological features of OA include the gradual loss of articular cartilage, osteophyte formation, joint space narrowing, and chronic synovial inflammation[89-91]. Given the inherently limited regenerative capacity of articular cartilage[92],the treatment of OA remains clinically challenging[93]. SSC have recently been recognized as a promising cellular therapy for OA due to their exceptional potential for cartilage regeneration[94].

In OA, SSCs contribute to the treatment of OA primarily through their multifaceted mechanisms involving chondrogenesis, anti-inflammation, and tissue repair[95]. SSCs differentiate into functional chondrocytes via the Wnt/TGF-β/BMP signaling pathway[72,96] and synthesize critical matrix components, such as collagen type II and proteoglycan, thereby effectively reconstructing the articular cartilage structure[3,97]. This process significantly enhances joint function and slows disease progression. By secreting paracrine growth factors like IGF and TGF-β[98-100], SSCs counteract chondrocyte apoptosis induced by pro-inflammatory factors such as TNF-α and IL-1β[101,102]. Additionally, the secretion of matrix metalloproteinase inhibitors helps maintain cartilage matrix homeostasis[103,104]. Moreover, SSCs promote angiogenesis and repair, improve the function of the joint synovial membrane, reduce synovial inflammation, regulate the microenvironment within the joint cavity, and enhance the production of lubricating fluid in the joint cavity, thereby alleviating joint friction and relieving pain[105].

The application of SSCs in OA demonstrates a promising and extensive potential. SSCs facilitate cartilage repair, suppress inflammatory responses, and enhance the joint microenvironment via the synergistic effects of multiple mechanisms (such as differentiation, paracrine signaling, anti-inflammatory actions, and metabolic regulation). These actions not only alleviate the symptoms of OA but also offer a potential novel strategy for its treatment.

Application in avascular necrosis of the femoral head

The application of SSCs in avascular necrosis of the femoral head primarily involves promoting bone tissue regeneration, enhancing blood supply, and modulating the micro-environment[106]. SSCs possess multilineage differentiation potential and can differentiate into osteoblasts to facilitate bone matrix deposition and mineralization, thereby repairing bone defects caused by ischemic necrosis[107]. Moreover, SSCs secrete a range of growth factors that stimulate angiogenesis, improve blood circulation, restore local oxygen and nutrient supply, and expedite bone healing[103].

SSCs also possess immunomodulatory functions, creating favorable conditions for bone repair by suppressing inflammatory responses and optimizing the immune microenvironment, thereby reducing local inflammation levels[108]. Simultaneously, SSCs can regulate the synthesis and remodeling of the extracellular matrix, promoting cell migration and proliferation while providing scaffolds for bone tissue regeneration[109]. Through the secretion of cytokines and chemokines, SSCs interact with surrounding cells, such as bone marrow MSC and osteoblasts, to modulate bone tissue growth and repair[76]. Moreover, SSCs can activate the body's self-healing mechanisms, enhancing endogenous stem cell activity and accelerating bone defect repair[110]. Studies have demonstrated that SSCs can form regenerative tissue resembling normal trabecular bone in the treatment of early focal avascular necrosis of the femoral head, further supporting their potential application in tissue-engineered bone[111]. Additionally, the combination of SSCs with impacted bone graft has been proven to be an effective therapeutic strategy. Analysis of recovered femoral head samples indicates that this tissue engineering approach can regenerate tissue with structure and function closely approximating normal trabecular bone, offering significant value for repairing a broader spectrum of bone defects[112].

The application of SSCs in the treatment of avascular necrosis of the femoral head can not only promote bone regeneration and repair, but also improve the therapeutic effect through multiple mechanisms such as improving the microenvironment and immune regulation. With further research, a better understanding of the mechanisms of stem cell therapy may drive its breadth and effectiveness in clinical applications.

Application of SSC in cartilage injury

Cartilage damage encompasses any structural impairment to cartilage tissue, including surface fissures, fibrosis, or localized shedding. Articular cartilage lacks intrinsic regenerative capacity and is typically replaced by mechanically inferior fibrocartilage following injury. Current interventions, such as subchondral bone drilling and osteochondral transplantation, offer only temporary relief[113]. Effective cartilage repair necessitates the coordinated action of cells, extracellular matrix scaffolds, and bioactive factors. While MSC possess the ability to differentiate into chondrocytes, their chondrogenic differentiation potential is constrained by variability in cell sources, passage-related attenuation, and imprecise regulation of growth factors[114-116]. In contrast, SSC exhibit distinct advantages in cartilage repair due to their robust self-renewal capacity and directed differentiation potential toward chondrogenesis. Cartilage injuries, encompassing conditions such as degenerative joint disease, traumatic cartilage damage, meniscus avascular zone repair, chondromalacia patellae, and intervertebral disc degeneration, involve the destruction of cartilage or fibrocartilage structures[117-119]. SSCs not only facilitate cartilage regeneration and minimize fibrous scar formation but also restore tissue architecture and function by enhancing extracellular matrix metabolism, inhibiting apoptosis, and delaying calcification[120-122]. Consequently, SSC-based therapies hold promise for restoring joint function in patients with cartilage-related disorders.

In the field of cartilage defects, partial or full-thickness defects are frequently associated with exposure of subchondral bone. Defects exceeding a critical size necessitate surgical intervention due to the loss of self-repair capability[123-125]. Traditional bone grafting methods exhibit limited efficacy in repairing such defects, and some studies have demonstrated that bone tissue engineering holds promise as an alternative approach for treating bone defects[126]. Researchers have enhanced the directed regeneration of MSC by encapsulating them within a 3D bio scaffold composed of alginate gel[127,128]. Furthermore, studies indicate that SSCs, owing to their robust chondrogenic differentiation potential and minimal immunogenicity[37], may address the limitations of MSCs when integrated with biological scaffolds, thereby offering a superior solution for cartilage defect repair.

Application of SSC in other diseases

SSC exhibit promising application value in the treatment of various diseases due to their multi-directional differentiation potential, self-renewal capacity, and immunomodulatory properties. In osteoporosis therapy, SSCs can differentiate into osteoblasts and suppress osteoclast activity, thereby restoring bone metabolic balance. Studies using animal models have demonstrated that SSC transplantation increases bone mineral density and mitigates trabecular microstructure damage. Furthermore, when combined with β-tricalcium phosphate scaffolds, the efficiency of osteogenic differentiation is significantly enhanced[129]. For intervertebral disc degeneration in spinal degenerative diseases, SSCs can differentiate into nucleus pulposus-like cells, promoting the synthesis of collagen type II and proteoglycan. Animal experiments indicate that SSC transplantation delays intervertebral disc degeneration, while its integration with a hydrogel delivery system improves cell survival within the disc environment[130]. In response to muscle atrophy or injury, SSCs stimulate muscle satellite cell activation and muscle fiber regeneration through paracrine signaling of IGF-1, HGF, and other factors. In muscular dystrophy models, SSC transplantation partially restores muscle function, and co-culture with myogenic precursor cells enhances myogenic differentiation[131,132]. In skin trauma and chronic ulcer treatment, SSCs secrete EGF, FGF, and other growth factors to promote keratinocyte migration and angiogenesis[133]. In diabetic foot ulcer models, local injection reduces inflammation and promotes granulation tissue formation. When combined with collagen scaffolds, SSCs improve retention rates and enhance repair outcomes[134,135]. In immune-related diseases, such as rheumatoid arthritis, SSCs regulate the Treg/Th17 balance, suppress proinflammatory cytokines, alleviate synovial hyperplasia and bone erosion, and exhibit superior cartilage protection compared to MSC[136,137]. In tumor-related bone diseases ,such as multiple myeloma or bone metastases, SSCs inhibit tumor cell proliferation and promote normal bone remodeling by competitively occupying the bone marrow microenvironment. Additionally, they may secrete DKK-1 antagonists to reverse osteolytic lesions. Genetically engineered SSCs can further enhance the anti-tumor bone destruction effect[138,139].

Stem cell technology has achieved remarkable advancements in the field of bone and joint injury repair, with a variety of emerging technologies offering novel directions for precision treatment. Gene editing technologies, such as CRISPR, can enhance the differentiation potential of stem cells into osteoblasts or chondrocytes by either knocking out or overexpressing specific genes, while simultaneously inhibiting inflammatory or fibrosis-related pathways. Epigenetic regulation technologies employ small molecule compounds or miRNAs to modulate chromatin accessibility in stem cells, thereby promoting osteogenic differentiation and suppressing adipogenic differentiation[140,141]. The HA/PLA composite scaffold fabricated via 3D bioprinting mimics the natural bone-cartilage interface through its gradient pore structure. When loaded with BMSCs, it induces directional osteogenesis via the integrin β1-FAK signaling pathway under dynamic compressive stress conditions in a bioreactor[142]. Exosome therapy functions by delivering functional molecules, such as synovial MSC-derived exosomes carrying miR-140-5p to inhibit MMP-13 expression. Engineered exosomes, modified with CD44 targeting molecules, are enriched on injured cartilage surfaces, enabling cell-free inflammation modulation and matrix repair[6,143]. Biomechanical regulation technology stimulates stem cell polarization toward the osteogenic lineage by upregulating mechanosensitive factors such as YAP/TAZ through in vitro fluid shear stress stimulation. This process is closely associated with chromatin remodeling, including H3K27acmodifications that enhance the activity of osteogenic gene promoters[144]. Collectively, these innovative technologies provide new opportunities for bone and joint injury repair by improving the efficiency of directed stem cell differentiation, enhancing local microenvironment regulation capabilities, and optimizing delivery strategies.

CONCLUSION

Bone and joint injuries are prevalent in orthopedics, and the treatment of cartilage injuries remains a significant challenge. While traditional non-surgical and surgical treatments have demonstrated some efficacy for mild injuries, their therapeutic effects are still limited for large cartilage defects or full-thickness injuries. In recent years, stem cell therapy, particularly the application of SSC, has emerged as a promising strategy for repairing bone and joint injuries. SSCs possess the capacity for self-renewal and multi-lineage differentiation, enabling them to differentiate into osteoblasts and chondrocytes, thereby promoting bone and cartilage regeneration. In conditions such as epiphyseal injury, OA, avascular necrosis of the femoral head, and cartilage damage, SSCs exert their effects through multiple mechanisms, including enhancing cartilage and bone tissue regeneration, modulating inflammatory responses, improving local blood supply, and inhibiting cell apoptosis. Notably, in the treatment of OA, SSCs not only promote cartilage regeneration but also exhibit anti-inflammatory and tissue repair properties, which improve joint function and slow disease progression. Furthermore, SSCs have shown superior bone regeneration capabilities in treating avascular necrosis of the femoral head, offering a novel therapeutic option for this condition.

Although SSCs have demonstrated significant potential in treating bone and joint injuries, their clinical application still encounters numerous challenges. First, achieving large-scale acquisition of SSCs while preserving their stemness remains an urgent issue to address, as this may compromise their biological functions during in vitro expansion. Second, the survival rate, differentiation efficiency, and integration of SSCs into host tissues in vivo require further optimization. Moreover, long-term safety concerns, such as the risks of heterotopic ossification or tumorigenesis, necessitate prolonged monitoring to ensure the feasibility and safety of clinical translation.

In the future, three key strategies should be implemented to optimize the clinical application of SSCs: (1) Utilizing biomimetic 3D systems and hypoxic conditions during culture, sequentially adding FGF-2/BMP-4 for expansion and Wnt3a/BMP-2 for differentiation, and employing small molecule regulation; (2) Establish a comprehensive system including genome monitoring, telomere detection, and cell purification in terms of safety, introducing suicide genes and prioritize autologous transplantation; and (3) Complete animal experiments prior to clinical translation, and establish a GMP-standard serum-free culture process to ensure consistent and controllable quality. Through these strategies, SSCs are expected to become a critical approach for treating bone and joint injuries. Moreover, an in-depth exploration of the molecular mechanisms and signaling pathways underlying SSCs will facilitate the development of more efficient stem cell therapies, thereby accelerating the clinical translation of regenerative medicine in orthopedics.

In summary, SSCs hold significant clinical potential for addressing bone and joint injuries. As technological advancements continue and research deepens, their application prospects will expand, offering patients more effective treatment options and ultimately enhancing their quality of life.