The influence of SDF-1 (CXCL12) gene in health and disease: a review of literature

Abstract

C-X-C motif chemokine ligand 12 (CXCL12), often referred to as stromal cell–derived factor 1 (SDF-1), is a crucial factor for musculoskeletal biology. SDF-1 is a powerful chemokine that has been shown to have a significant impact on a variety of physiological functions, including tissue repair, homeostasis maintenance, and embryonic development. SDF-1 plays a dominant role in bone and cartilage metabolism. It directs mesenchymal stem cell migration, controls osteogenesis and chondrogenesis, promotes angiogenesis, and modifies the inflammatory environment. SDF-1 also acts as an inflammatory chemokine during joint inflammation, recruiting inflammatory mediators to act and cause bone and cartilage degradation, thus causing osteoarthritis. Age-related bone loss and osteoporosis is exacerbated by SDF-1, which is elevated in the peripheral circulation due to a phenomenon known as “senescence associated secretory phenotype” of SDF-1. SDF-1 is also implicated in cancer metastasis causing the spread of secondary malignancies. Thus, the aim of this review is to explore the complex methods by which SDF-1 affects the fine equilibrium of bone and cartilage metabolism, providing insight into its importance in both healthy and diseased conditions.

Introduction

Chemokines are small, highly charged molecules that are either membrane-bound or released and have a molecular weight of 6–14 kDa (Baggiolini et al. 1997). Chemokines are proinflammatory cytokines because they can express themselves in inflammatory environments and attract leukocytes that mediate inflammatory reactions. They are not strictly pro inflammatory but also participate in cell/tissue homeostasis by regulating immune surveillance. One of these functions is the trafficking (circulation, recruitment, and dissemination) of immature lymphocytes and blood cells (Bajetto et al. 2001; Kim and Broxmeyer 1999). According to their structure, chemokines are categorized into four primary categories, CXC, CC, C, and CX3C, which can also be represented by Greek symbols such as α, β, γ, and δ (Bajetto et al. 2001). C chemokines have only two conserved cysteines and the others, CXC, CC, and CX3C, all have four. The first two cysteines in CC chemokines are near each other. In CXC, the first and second cysteines are separated by one amino acid. In CX3C, the first and second cysteines are separated by three amino acids. Specific receptors that belong to the seven-transmembrane receptor superfamily and interact with one another through coupled heterotrimeric G proteins mediate the activity of chemokines (Fig. 1). There are currently 18 known chemokine receptors: 6 CXC (CXCR 1–6), 10 CC (CCR 1–10), 1 CX3C (CX3CR1), and 1 C (XCR1) receptors (Bajetto et al. 2001; Horuk 2001).

Fig. 1.

Classification of the chemokine family by structure. Dots denote various amino acids; C stands for cysteine; X is an amino acid that is not cysteine

The CXC or alpha family, which includes stromal cell–derived factor‑1 (SDF-1), is identified by the single amino acid that separates the first two cysteines (Juarez et al. 2004). The stromal cell line ST2 generated from bone marrow (BM) was first used to clone SDF-1 (Shirozu et al. 1995; Tashiro et al. 1993). It was subsequently discovered to be a pre-B cell growth-stimulating factor (Nagasawa et al. 1994).

SDF-1 influences a number of physiological processes, including embryonic development and organ homeostasis. It is secreted by various organs such as the lungs, liver, bone marrow, and skin. SDF-1 is a powerful chemokine that has been shown to have a significant impact on a variety of physiological functions, including tissue regeneration and repair, chemotaxis and homeostasis maintenance, and embryonic development and organogenesis. It is crucial for the attraction, localization, maintenance, growth, and differentiation of musculoskeletal system progenitor stem cells as well as in various pathological conditions such as osteoarthritis, osteoporosis, sarcopenia, and cancer. Thus, the aim of this review is to discuss the various functions and roles of SDF-1 and CXCR4. Additionally, it provides evidence linking the SDF-1/CXCR4 signaling pathway to several physiological and pathological events related to the body.

Structure

The structure of SDF-1, also known as C-X-C motif chemokine ligand 12 (CXCL12), refers to its molecular composition and arrangement. CXCL12 is a small protein composed of 89 amino acid residues. Human SDF-1 has six subtypes, i.e., SDF-1α (89 amino acids), SDF-1β (93 amino acids), SDF-1γ (119 amino acids), SDF-1δ (140 amino acids), SDF-1ε (90 amino acids), and SDF-1φ (100 amino acids), as shown in Fig. 2 (Döring et al. 2014). They have a common N-terminal amino acid sequence, but a different C-terminus amino acid sequence.

Fig. 2.

Six isoforms of SDF-1. They have a common N-terminal amino acid sequence (1–88), but a different C-terminus amino acid sequence. Letters indicate the specific amino acids. (glycine, G; alanine, A; leucine, L; methionine, M; phenylalanine, F; tryptophan, W; lysine, K; glutamine, Q; glutamic acid, E; serine, S; proline, P; valine, V; isoleucine, I; cysteine, C; tyrosine, Y; histidine, H; arginine, R; asparagine, N; aspartic acid, D; threonine, T)

There are two primary isoforms of SDF-1: SDF-1α, which is the most common and comprises 89 amino acids, and SDF-1β, which differs by 4 additional amino acids due to alternate splicing at the C-terminal end (Juarez et al. 2004; Shirozu et al. 1995). The structure of SDF-1 is characterized by its folding pattern, which gives rise to its three-dimensional conformation. The protein adopts a three-dimensional compact structure with an arrangement of alpha helices and beta strands (Crump et al. 1997; Dealwis et al. 1998; Thomas et al. 2017). These secondary structural elements contribute to the overall stability and function of the protein. Notably, while the primary structure of SDF-1 is well defined, the specific tertiary structure (the 3D arrangement of the protein) may vary depending on the experimental conditions and the presence of other molecules, such as ions or receptors, that interact with SDF-1. Many tissues, such as the brain, heart, kidney, thymus, liver, lung, lymph nodes, bone marrow, pancreas, spleen, ovary, and small intestine, constitutively express SDF-1 (Nagasawa et al. 1994; Shirozu et al. 1995; Tashiro et al. 1993; Thomas et al. 2017). SDF-1 only possesses one receptor, C-X-C motif chemokine receptor 4 (CXCR4), which was initially discovered to be a coreceptor for human immunodeficiency virus (HIV) strains that are T cell line-tropic (Jazin et al. 1997). SDF-1 interaction with CXCR4 results in a variety of biological effects, some of which depend on the cell type and include an increase in integrin-mediated adhesion, chemotaxis, migration, enhanced survival, proliferation, and apoptosis (Horuk 2001).

Functions

Some of the known functions of SDF-1 are described as follows. They are summarized in Table 1.

Table 1.

A summary of the various functions and roles of SDF-1 according to various authors

Functions of SDF-1 gene	Function	Authors
Chemotaxis	SDF-1 acts as a chemoattractant, guiding the migration of cells toward areas with higher SDF-1 concentrations	Dar et al. 2006; Ito 2011; Shyu et al. 2006
Hematopoiesis	The survival, growth, and differentiation of hematopoietic stem cells into distinct blood cell lineages are all regulated by SDF-1	Fröbel et al. 2021; Sugiyama et al. 2006; Wang and Wagers 2011
Angiogenesis	SDF-1 attracts nucleus pulposus cells (NPCs) to sites of tissue injury or hypoxia, facilitating the growth of blood vessels and revascularization	Zhang et al. 2020
Development and organogenesis	SDF-1 contributes to the development and organogenesis of various tissues and organs	Katsumoto and Kume 2013; Nagasawa et al. 1996; Sapède et al. 2005; Tachibana et al. 1998; Zou et al. 1998
Tissue repair and regeneration	SDF-1 aids tissue healing and regeneration by helping to recruit stem and progenitor cells to the area of damage	Yuan et al. 2013
Immune response	SDF-1 helps regulate the trafficking and positioning of immune cells within tissues	Isaacson et al. 2017; Schiwon et al. 2014
Bone remodeling, repair, osteogenesis, and chondrogenesis	The regulatory chemokines SDF-1 (CXCL12) and CXCR4 are crucial for the attraction, localization, maintenance, growth, and differentiation of musculoskeletal system progenitor stem cells	Gilbert et al. 2019
Cancer metastasis	While the SDF-1-CXCR7 axis is involved in angiogenesis and tumor formation, the SDF-1-CXCR4 axis stimulates the homing process by controlling cellular secretion and cell adhesion molecules	Burns et al. 2006
Musculoskeletal diseases	Senescence-associated secretory phenotype causes SDF-1 levels to increase in plasma and decrease in bone marrow further causing osteoporosis	Gilbert et al. 2019
Therapeutic application and future perspective	Scaffolds containing SDF-1 were engineered to provide a regulated release of this chemokine, which would draw in circulating or transplanted CD34 + stem cells and promote in situ tissue regeneration	Lau and Wang 2011

SDF-1 and chemotaxis

SDF-1 acts as a chemoattractant, guiding the migration of cells toward areas with higher SDF-1 concentrations (Dar et al. 2006; Ito 2011; Shyu et al. 2006). It primarily attracts stem cells, immune cells, and progenitor cells. Sperm can be drawn toward a single bovine cumulus-oocyte complex (COC), indicating that the COC releases sperm chemoattractants to draw them toward it. SDF-1 is seen in COCs, and its receptor, CXCR4, is seen in sperm, which has proven to be a potential chemoattractant (Umezu et al. 2020). Neural crest cells infiltrate inhibitor-free extracellular matrix corridors where Eph-ephrins group these cells into subpopulations. Once neural crest cells enter the extracellular matrix, they are ultimately activated by attractants such as SDF-1 or vascular endothelial growth factor A (VEGF-A) (Bajanca et al. 2019). In the central nervous system (CNS), stem cells are present throughout life in the prosencephalon region and continue to produce neurons and glia in the hippocampal dentate gyrus and the subventricular zone (SVZ). Different kinds of CNS cell migration have been linked to SDF-1/CXCR4 signaling. Immunohistochemistry of the SVZ revealed that SDF-1 is expressed by ependymal cells and by the vasculature, two critical SVZ niches, thus causing the migration of CNS cells (Kokovay et al. 2010). SDF-1 also controls how multiple myeloma cells are directed to the bone marrow (Azab et al. 2009). Ras-related C3 botulinum toxin substrate 1 (Rac1) and Ras homolog gene family, member A (RhoA) GTPases, cause multiple myeloma cell adhesion, and their chemotaxis is affected by SDF-1. Thus, both Rac1 and RhoA play important roles in the SDF-1-induced adherence of multiple myeloma cells. Additionally, it has been demonstrated that SDF-1 promotes multiple myeloma cell proliferation by upregulation of very late activation antigen-4 (VLA-4) and mediates cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1). This enhances chemotaxis, invasion, and actin polymerization in multiple myeloma cells (Parmo-Cabañas et al. 2004).

SDF-1 and hematopoiesis

The production of new blood cells, or hematopoiesis, is regulated in part by SDF-1. The survival, growth, and differentiation of hematopoietic stem cells into distinct blood cell lineages are all supported by this process. Hematopoietic stem and progenitor cells (HSPCs) interact with bone marrow stromal cells (BMSCs) to determine their fate (Bessy et al. 2021). HSPCs polarize in contact with BMSCs in response to SDF-1. The primary chemoattractant for murine hematopoietic stem cell homing and maintenance is the chemokine CXCL12 (SDF-1), which is the ligand of CXCR4 (Fröbel et al. 2021; Sugiyama et al. 2006; Wang and Wagers 2011). The vascular network and the bone matrix in the bone marrow function as local niches that transmit unique signals through SDF-1 that control the quiescence, proliferation, and differentiation of HSPCs. Elevation of SDF-1 levels in the blood causes VEGF-A-mediated increase in megakaryocytes which causes an increase in platelet formation. It is one of the first chemokines associated with the megakaryocyte-mediated platelet formation (Thon 2014).

SDF-1 and angiogenesis

The process of angiogenesis, or the development of new blood vessels, is greatly aided by SDF-1 (Petit et al. 2007). SDF-1 attracts nucleus pulposus cells (NPCs) to sites of tissue injury or hypoxia, facilitating the growth of blood vessels and revascularization. It causes the proliferation and angiogenesis of vascular endothelial cells (VECs), causing their migration and invasion to form new blood vessels. In degenerated discs, the SDF-1/CXCR4 axis in primary NPCs increases angiogenesis. It is done by regulating the PTEN/phosphatidylinositol-3-kinase/AKT pathway (Zhang et al. 2020). Ischemia increases SDF-1 levels. This leads to increased endothelial progenitor cells (EPCs) leading to angiogenesis via a heme oxygenase 1–dependent mechanism in the injured tissue (Deshane et al. 2007).

SDF-1 and development and organogenesis

SDF-1 contributes to the development and organogenesis of various tissues and organs. It guides the migration of cells during embryonic development, ensuring proper tissue patterning and organ formation. SDF-1 plays a significant role in developing the central nervous system, cardiovascular system, and vascular system, among other structures. FGF regulates expression of SDF-1α and its receptors CXCR4a, CXCR4b, and CXCR7. Through this expression, SDF-1 aids in tissue regeneration (Bouzaffour et al. 2009). It also plays a very important role in embryonic development. Mutations in the SDF-1 or CXCR4 genes are lethal in response to defects in neurogenesis, angiogenesis, cardiogenesis, myelopoiesis, lymphopoiesis, and germ cell development (Katsumoto and Kume 2013; Nagasawa et al. 1996; Sapède et al. 2005; Tachibana et al. 1998; Zou et al. 1998). During pancreas development, the CXCL12-CXCR4 signaling pathway is responsible for spatiotemporal repositioning of hemangioblasts. It has the function of stimulating the pancreas. CXCL12-CXCR4 signaling does not directly affect pancreatic and duodenal homeobox 1 (PDX1) (pancreatic tissue) expression in the early pancreas. It acts indirectly by directing the migration of hemangioblasts during pancreatic development (Katsumoto and Kume 2013). During the development of the heart, coronary arteries arise from the peripheral truncal nerve plexus. It has a ring-shaped network of capillaries that penetrate the aortic wall. SDF-1 levels were elevated in the aortic duct. Peripheral truncal endothelial cells express CXCR4. Therefore, it plays an important role in the development of nerves (Ivins et al. 2015).

SDF-1 and tissue repair and regeneration

SDF-1 plays a role in tissue repair and regeneration. It aids tissue healing and regeneration by helping to recruit stem and progenitor cells to the area of damage (Fig. 3). Low-level stress increases the release of SDF-1, which in turn causes human mesenchymal stem cells (HMSCs) to express its receptor CXCR4 until the cells completely cover the wound, thus promoting regeneration and repair (Yuan et al. 2013). Tissue repair occurs through a complex series of therapeutic actions involving growth factors/cytokines.

Fig. 3.

Mechanism of tissue repair and regeneration. In response to cell injury, chemokine SDF-1 is released which attracts stem cells, and immune and progenitor cells, to the site of injury to aid tissue repair and regeneration

SDF-1 and CXCR4 interaction is essential for homeostatic regulation of white blood cell trafficking, blood cell production, organ development, cell differentiation, and tissue repair in response to molecules causing inflammation. The mechanism of high mobility group box-1 (HMGB1)–mediated stem cell mobilization is like recruitment of inflammatory cells to wounded tissues for white blood cell trafficking and homing. HMGB1 inhibits SDF-1 degradation by causing molecular interactions that are both functional and physical (Haque et al. 2020). Thus, the CXCR4-SDF-1-HMGB1 pathway causes directional migration of cells and regeneration of affected organs by working in conjugation with one another.

The regulation of muscle repair by CXCR4/SDF-1 is dependent on Matrix metalloproteinases (MMP)-10 activity (Bobadilla et al. 2014). Thus, effective skeletal muscle renewal depends on the modulation of CXCR4/SDF-1 communication, which is governed by MMP-10 activity. SDF-1 binding to the CXCR4 receptor enhances skeletal muscle regeneration. It increases cluster of differentiation (CD)9 expression. Thus, it influences stem cell recruitment to damaged muscles (Brzoska et al. 2015). An increase in the production of key trophic factors such as SDF-1, CXCL12, fibroblast growth factor (FGF), hepatocyte growth factor, insulin-like growth factor (IGF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in the muscle after VEGF injection is what causes the organ repair mechanism. Induction of muscle-derived trophic factors appears to affect the skeletal and myocardial compartments by activating myeloid progenitor cells and expanding progenitor cells, both of which are important for myocardial regeneration (Zisa et al. 2011). The overall effects of SDF-1 gene in tissue regeneration and repair are summarized in Table 2.

Table 2.

A summary of the effects of SDF-1/CXCR4 in tissue repair and regeneration according to various authors

Effect of SDF-1/CXCR4 in tissue repair and regeneration	Reference
Recruitment of stem and progenitor cells to damaged area	Yuan et al. 2013
Homeostatic regulation of white blood cell trafficking, organ development, and tissue repair	Haque et al. 2020
Promotion of directional migration of cells and organ regeneration	Haque et al. 2020
Modulation of muscle repair dependent on MMP-10 activity	Bobadilla et al. 2014
Enhancement of skeletal muscle regeneration and stem cell recruitment to damaged muscles with increase CD9 expression	Brzoska et al. 2015
Increase in production of key trophic factors like FGF, HGF, IGF, NGF, and VEGF for tissue repair	Zisa et al. 2011

SDF-1 and the immune response

SDF-1 plays a role in immune responses. It attracts immune cells to sites of inflammation or infection. SDF-1 helps regulate the trafficking and positioning of immune cells within tissues. In addition to its role as a T cell chemoattractant, SDF-1 may also have more basic immunoregulatory functions, such as promoting T cell proliferation and cytokine production and preventing activation-induced T cell apoptosis (Dunussi-Joannopoulos et al. 2002). During a urinary tract infection caused by Escherichia coli (E. coli), inflammatory sites contain a range of signaling molecules, including various cytokines and chemokines. Immediately after infection, bladder epithelial cells secrete SDF-1, which initiates immune cell accumulation at the site of infection. It has been demonstrated to have a role in the recruitment of phagocytic cells to the bladder infection site (Isaacson et al. 2017; Schiwon et al. 2014).

SDF-1 and bone remodeling, repair, osteogenesis, and chondrogenesis

The regulatory chemokines SDF-1 (CXCL12) and CXCR4 are crucial for the attraction, localization, maintenance, growth, and differentiation of musculoskeletal system progenitor stem cells (Gilbert et al. 2019). Multipotent stem cells (MSCs) are used to differentiate bone, cartilage, fat, and tendon and muscle. During bone repair or remodeling, SDF-1 is produced by MSCs and osteoblasts in response to injury. It acts as a chemoattractant, recruiting MSCs and other cells to the site of injury. MSCs have CXCR4 receptors on their surface, and when SDF-1 binds to CXCR4, it triggers signaling pathways that promote the migration and differentiation of MSCs into osteoblasts, which are responsible for bone formation as shown in Fig. 4. The expression of CXCL12 and its receptor CXCR4 are two chemical signals that are used by MSCs to attract them to their target area. MSCs are crucial for the formation of scaffolds prior to accessing groups of tissues of the musculoskeletal system, making them particularly significant in this regard.

Fig. 4.

SDF-1 in osteogenesis. SDF-1 is released to differentiate mesenchymal stem cells into bone precursors (osteogenic differentiation) and vascular precursors (angiogenic differentiation) which aid in mature bone formation

Local administration of SDF-1 considerably increases bone marrow stem cell recruitment, promotes greater bone repair, and increases the expression of osteocalcin and Runt-related transcription factor 2 (RUNX2) (Liu et al. 2020). Platelet-derived growth factor (PDGF) and SDF-1 promote endogenous cell recruitment and cartilage matrix synthesis (Guo et al. 2023).

In tests on the regulation of chondrocyte proliferation, SDF-1 yielded varying outcomes (Li et al. 2021). Some in vitro studies have shown that impeding SDF-1 expression and upregulation could promote the proliferation of chondrocytes. Through various pathways, inhibition of SDF-1 promoted an increase in cartilage and chondrocyte proliferation and chondrocyte development and maturation. MicroRNA (miR) miR-3 and miR-211–3p directly targeted and inhibited SDF-1 to enhance chondrocyte proliferation, viability, and migration (Dai et al. 2019; Zheng et al. 2017). Through the mitogen-activated protein kinase (MAPK) MAPK/p381 and all-trans retinoic acid (ATRA) pathways, high concentrations of SDF-1 induce chondrocyte apoptosis and necrosis (Wei et al. 2006; Hu et al. 2017). All these pathways showed a negative correlation between SDF-1 and chondrogenesis.

In vivo studies have demonstrated a positive correlation between cartilage proliferation and SDF-1 expression (Li et al. 2021). Through the nuclear factor kappa-B (NF-kB) and extracellular signal–regulated kinase (Erk)1/2 pathways, SDF-1 promoted the overexpression of cyclin D1. Two key transitions occur during the endochondral ossification process: the entry of chondrocytes into the hypertrophy phase from the proliferative phase and the passage of chondrocytes from the hypertrophic phase to the ossification phase. In contrast to proliferating chondrocytes, hypertrophic chondrocytes have a much greater expression of CXCR4, and SDF-1 is detected in the growth plate. SDF-1 controls chondrocyte hypertrophy to promote bone development (Li et al. 2021).

Synovial membranes close to articular cartilage contain the chemokine SDF-1, which is linked to inflammation (Thomas et al. 2017). Osteoarthritis is an aseptic inflammation of bone. Studies have demonstrated the ability of SDF-1 to control osteogenic differentiation (Yang et al. 2020). SDF-1 was found to be mostly expressed in the bone marrow, while CXCR4 was found in the hypertrophic layer of cartilage. Continuous force on the temporomandibular joint (TMJ) caused from overloaded functional orthopedics of the joint with mandibular advancement appliance causes cartilage to degrade with increased release of the tissue-destructive enzyme MMP13 and decreased expression of collagen II. It also enhanced the microRNA (mRNA) and protein expression of SDF-1 and CXCR4. These findings suggest that enhanced osteoblast-derived SDF-1 expression may improve osteogenic differentiation as well as the ability of SDF-1 to bind CXCR4 and degrade cartilage (Yang et al. 2020).

The use of stem cells in therapy holds promise for the healing of damaged tissue. Under the control of the SDF-1/CXCR4 axis, stem cells have homing properties and can be recruited to damage sites after activation (Wang et al. 2022). Several combinations, such as SDF-1 and polylactic-co-glycolic acid (PLGA) microspheres loaded with Kartogenin (KGN); immobilized bone morphogenic protein (BMP)-7 with SDF-1 in polylactic acid (PLA) cylinder; gel/HA copolymer combined with hydroxyapatite (HAP), hyaluronic acid (HA), and SDF-1 (Gel/HA-HAP-SDF-1); or platelet-rich fibrin scaffold containing SDF-1 were used for bone and cartilage regeneration to aid in recruiting stem cells to the injected sites (Bahmanpour et al. 2016; Chang et al. 2021; Dong et al. 2021; Lauer et al. 2020). This could promote cartilage regeneration. SDF-1 supplementation has an osteoinductive effect, causing new bone to develop with greater strength. All these studies may open up new possibilities for its use in regenerating bone tissue.

Studies have also shown that SDF-1/CXCR4 and regulated upon activation, normal T cell expressed and secreted (RANTES)/C–C chemokine receptor type 1 (CCR1), mediate the recruitment of exogenous BMSCs to osteoarthritic lesion sites where the recruited BMSCs differentiate into chondrocytes to repair osteoarthritic-like lesions (Lu et al. 2015a, b). SDF-1 levels increase in patients with disordered occlusion (Kuang et al. 2013, 2019). Chondrocytes might express more pro-osteoclastic factors when mechanically stimulated, which leads to condylar subchondral bone resorption by encouraging osteoclastogenesis (Kuang et al. 2019). The middle and posterior thirds of the condylar cartilage displayed local pathologic alterations in the experimentally induced disordered occlusion group. Moreover, uneven cellular disposition, cell-free regions, and a loss of cartilage surface integrity are degenerative alterations. The expression of SDF-1 increases in the hypertrophic layers of the cartilage and bone marrow regions. SDF-1 was less abundant in the condylar cartilage than in the bone marrow region next to the hypertrophic layer of the normal mandibular condyle.

The SDF-1/CXCR4 axis is activated when aberrant tensile stress occurs because SDF-1 has the ability to upregulate a particular CXCR4 receptor, which improves the binding efficiency of the receptor (Bin et al. 2014). Cartilage tissue is directly damaged by this condition, which also increases the expression of interleukin (IL)-6 and other inflammatory factors. This harm directly promotes chondrocyte hypertrophy, which increases collagen X expression, promoting repair. In contrast, a study by Rapp et al. (2015) showed that systemically injected MSCs attracted and supported bone development only in cases of injury and not under mechanical loading to induce bone formation. Cells close to the injury site significantly express SDF-1 or CXCL-12, but when noninvasive mechanical loading was applied, mesenchymal stem cell recruitment was not detected, suggesting an inactive role of SDF-1. Studies have also shown that mechanical stresses cause periodontal ligament (PDL) tissues to secrete SDF-1. Thus, SDF-1 may play a significant role in the maintenance of alveolar bone metabolism by binding to its receptor CXCR4 in mesenchymal stem cells in the bone marrow and stimulating osteoblast development, thus promoting bone and PDL regeneration (Goto et al. 2021; Xu et al. 2019).

Thus, SDF-1 is strongly expressed in cartilage and bone. It acts as an inflammatory chemokine during joint inflammation, recruiting inflammatory mediators to act and cause bone and cartilage degradation (Bragg et al. 2019; Kanbe et al. 2002, 2004; Wang et al. 2015, 2018, 2020). Owing to its chemotactic properties, it also recruits mesenchymal cartilage and bone stem cells to enhance bone development and promote chondrogenic and osteogenic differentiation (He et al. 2018; Huang et al. 2022; Lu et al. 2016; Wang et al. 2017a, b; Zhang et al. 2014; Zhang et al. 2023). However, the role of SDF-1 is more involved in bone formation than in cartilage formation. The overall effects of SDF-1 gene on the musculoskeletal system are summarized in Table 3. Thus, the SDF-1-CXCR4 axis promotes osteogenesis and the rapid formation of bone from cartilage.

Table 3.

A summary of the effects of SDF-1/CXCR4 in skeletal system according to various authors

Effect of SDF-1/CXCR4 in skeletal system	Reference
Increased bone marrow stem cell recruitment, greater bone repair, increased expression of osteocalcin, and RUNX2	Liu et al. 2020
Promotion of endogenous cell recruitment and cartilage matrix synthesis	Guo et al. 2023
Regulation of chondrocyte proliferation with varying outcomes	Li et al. 2021
Inhibition of SDF-1 expression promoting chondrocyte proliferation and maturation	Dai et al. 2019; Zheng et al. 2017
Induction of chondrocyte apoptosis and necrosis at high concentrations	Wei et al. 2006; Hu et al. 2017
Promotion of cartilage proliferation and bone development	Li et al. 2021
Control of chondrocyte hypertrophy to promote bone development	Li et al. 2021
Link to inflammation in synovial membranes	Thomas et al. 2017
Control of osteogenic differentiation and osteoarthritis	Yang et al. 2020
Recruitment of exogenous BMSCs to osteoarthritic lesion sites for repair	Lu et al. 2015a, b
Role in disordered occlusion and chondrocyte hypertrophy	Kuang et al. 2013; Kuang et al. 2019
Upregulation in response to aberrant tensile stress	Bin et al. 2014
Role in alveolar bone metabolism and PDL regeneration	Goto et al. 2021; Xu et al. 2019
Inflammatory chemokine role during joint inflammation	Bragg et al. 2019; Kanbe et al. 2002; Kanbe et al. 2004; Wang et al. 2015; Wang et al. 2018; Wang et al. 2020

SDF-1 and cancer metastasis

SDF-1 is implicated in cancer metastasis, the progression of secondary malignant growth away from the primary cancer site. It attracts cancer cells expressing the CXCR4 receptor, which is the receptor for SDF-1, to tissues expressing high levels of SDF-1. This interaction promotes the migration and invasion of cancer cells, contributing to metastasis. A crucial transcription factor called nanog homeobox protein (h-NANOG) which contains a homeodomain is needed to maintain pluripotency in embryonic stem cells. By controlling CXCR4 expression to mediate glioblastoma, Sánchez-Sánchez et al. (2021) demonstrated that h-NANOG was a mediator of cellular migration via the SDF-1/CXCR4 pathway. Many different forms of human malignancies, including those of the lung, mouth, prostate, stomach, breast, and brain, have been shown to have elevated NANOG expression. While the SDF-1-CXCR7 axis is involved in angiogenesis and tumor formation, the SDF-1-CXCR4 axis stimulates the homing process by controlling cellular secretion and cell adhesion molecules (Burns et al. 2006). CXCR4 antagonists (AMD3100, T140, and TN14003) have been shown to effectively block the SDF-1/CXCR4 axis. They block this axis by competing with CXCR4 for its ligand SDF-1. They are being utilized to treat HIV infection in addition to numerous malignancies (Burger et al. 2011; Tamamura et al. 2001; Green et al. 2016; Wang et al. 2017a, b).

SDF-1 and musculoskeletal diseases

The most common musculoskeletal conditions in the world are osteoporosis and sarcopenia. These conditions are the primary cause of disability globally. Increased blood levels of inflammatory cytokines are linked to aging, and these levels can have a variety of pleiotropic impacts on cellular processes, including a reduction in MSC viability for differentiation and regeneration. In particular, SDF-1 plays a critical role in bone and muscle BMSC recruitment, survival, and engraftment. However, with aging, the levels of SDF-1 were elevated in plasma and not bone marrow. Increased plasma levels may accelerate bone deterioration and lower bone marrow density, raising the risk of osteoporosis because SDF-1 is also associated with osteoclast recruitment. Thus, the impact of aging-related inflammation on SDF-1 levels may be involved in the pathological alterations associated osteoporosis. Chronic diseases including osteoporosis and higher mortality have been linked to the “senescence-associated secretory phenotype” (SASP). Consequently, a rise in SASP cells may result in a drop in SDF-1 levels in the bone marrow (Gilbert et al. 2019). Similarly in osteoarthritis and rheumatoid arthritis, serum levels of SDF-1 increase causing an increase in concentration of inflammatory mediators like MMP-1, 3, 9, and 13 (Gilbert et al. 2019).

Sarcopenia is a progressive, age-related decrease of muscle mass that is widespread and linked to compromised muscle function. Signal transducer and activator of transcription 3 (STAT-3) signaling pathway that mediates cytokines and growth factors promotes the myogenic lineage of cells by faster differentiation of satellite cells. By promoting satellite cell self-renewal, SDF-1 may prevent constitutive activation of STAT-3 and slow the onset of sarcopenia (Gilbert et al. 2019).

Therapeutic application and future perspective

In order to offer more effective treatment options, therapeutic techniques utilizing SDF-1 have emerged. These strategies involve the regulation of signaling pathways to enable the use of biomaterials and multipotent stem/progenitor cells. Bone marrow CD34 + stem cells are activated by SDF-1. The SDF-1-CXCR4 axis uses a chemotactic gradient to guide stem cells to specific targets or damaged areas (Lau and Wang 2011). Stem cell regeneration therapy has a lot of potential when it comes to bone marrow MSC transplantation into tissue. The donor cell’s inability to live long enough to integrate into tissue is a significant obstacle. It is believed that factors like hypoxia, free radical oxidation, and inadequate nutrition leading to cellular death are to blame for the poor survival of transplanted cells. It is interesting to note that MSCs exposed to high SDF-1 levels show enhanced cellular growth potential, apoptosis prevention, and transplanted MSC survival (Herberg et al. 2013). Degradation of the mitochondrial membrane and subsequent release of cytochrome c, two powerful inducers of apoptosis, were greatly reduced after SDF-1 was administered (Yin et al. 2011). Owing to its angiogenic properties, it can also indirectly influence the vascularity of the MSCs. These results point to the potential application of SDF-1 to improve current stem cell therapy, and concrete developments include the creation of genetically modified MSC with conditional expression of SDF-1. Scaffolds containing SDF-1 were engineered to provide a regulated release of this chemokine, which would draw in circulating or transplanted CD34 + stem cells and promote in situ tissue regeneration (Lau and Wang 2011). SDF-1 can be delivered as direct injections, in the form of scaffolds with microdelivery system; gelatin hydrogels; polylactide ethylene oxide fumarate (PLEOG) hydrogels, in the form of gene modification using adenoviral, retroviral, or lentiviral vector; and polyethylene glycolated fibrin patches (Lau and Wang 2011). Regenerative medicine utilizing SDF-1 has already started to be explored. It is therefore possible that in the near future, its application in a clinical context may become widely accepted.

Conclusion

In summary, it is indisputable that stromal cell–derived factor 1 (SDF-1) plays a critical role in the metabolism of bone and cartilage. SDF-1 has become an important regulator in preserving musculoskeletal homeostasis, controlling everything from the migration of mesenchymal stem cells to the regulation of osteogenesis, chondrogenesis, and angiogenesis as well as the modulation of the inflammatory response. Its complex roles highlight its importance in pathological disorders like osteoporosis and osteoarthritis as well as physiological processes like development and tissue regeneration. Aiming for the restoration of musculoskeletal health and the prevention of related illnesses, targeting this chemokine pathway offers promise as research into the complex processes underlying SDF-1’s activities continues. This chemokine has influenced a wide range of tailored regenerative medicine procedures. SDF-1 incorporated scaffolds and gene modifications using viral vectors have been designed to gain a controlled release of SDF-1 to attract and stabilize MSCs during tissue regeneration. Understanding the complexity of SDF-1’s influence opens new avenues for clinical interventions, fostering a deeper understanding of musculoskeletal biology and paving the way for enhanced patient care and treatment outcomes.

Author contribution

A.P. contributed to the study conception and design and critically revised the work. Data collection and drafting of the manuscript was performed by S.B. V.S. revised the manuscript text. All the authors read and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

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Consent to participate

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Consent for publication

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Conflict of interest

The authors declare no competing interests.

Disclosure

Data for the preparation of this manuscript utilizes thorough research and reading of articles and is a compilation of well-integrated citations. However, we intend to disclose that ChatGPT and QuillBot paraphrasing tool were utilized to generate synonyms and lightly edit the writing of the manuscript without altering the information that has been provided in this review. Also, all diagrams are drawn using Microsoft PowerPoint.