Introduction
Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or basement membrane protein 40 (BM40), is a 32 kDa calcium-binding matricellular protein prevalent in both mineralized and non-mineralized tissues. Initially believed to be specific to mineralized tissues, SPARC has since been found in a variety of tissues. Its expression typically aligns with fibrillar collagens, particularly collagen type I, the main component of the pre-mineralized bone matrix. The mechanical properties of bone are attributed to the mineral composition of the osteoid, primarily hydroxyapatite (HA), which mineralizes the collagenous matrix. SPARC contains domains for binding both collagen and HA, suggesting a role in enhancing the mineralization of the collagen matrix. Despite its known functions, the full scope of SPARC's role in mineralized tissues, especially during homeostasis and disease, remains to be fully elucidated.
Fig. 1 Schematic of SPARC Activity in Formation of Mineralized Matrix (Rosset E. M.; Bradshaw A. D. 2016).
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Structural Features and Expression
SPARC is encoded by a single gene producing a secreted, monomeric, glycosylated polypeptide with four defined domains: an N-terminal calcium-binding domain, a cysteine-rich domain, a hydrophilic region, and an extracellular Ca2+ domain with an E-F hand motif at the C-terminus. The human SPARC gene is located on chromosome 5q31-q33 and contains 10 exons and 9 introns. SPARC undergoes differential glycosylation depending on tissue-specific expression, with the bone-specific form showing higher collagen affinity.
SPARC is secreted by osteoblasts during bone formation. Its collagen-binding domain is separated from the hydroxyapatite-binding site, potentially facilitating collagen mineralization. High SPARC levels are observed in immature bone and decrease in mature bone. SPARC is expressed in various cell types in mineralized tissues, including osteoblasts, endothelial cells, and fibroblasts. Additionally, SPARC is involved in regulating cell attachment, spreading, and proliferation in vitro, influencing matrix metalloproteinase activity and interacting with growth factors.
SPARC in Procollagen Processing and Fibril Assembly
Collagen, the primary structural component of the extracellular matrix (ECM), exists in numerous types, with collagen I being the most abundant in mammalian tissues. SPARC interacts with various collagens (I, III, IV, and V), implicating it significantly in ECM assembly. Procollagen I, the precursor to collagen I, undergoes extensive post-translational modifications before being incorporated into insoluble collagen fibrils via N- and C-terminal propeptide cleavage.
Studies have demonstrated that SPARC-null mice show decreased collagen content in bone and other connective tissues. Overexpression of SPARC increases collagen-rich ECM assembly, while its absence leads to less efficient collagen incorporation into insoluble fibrils. Additionally, SPARC may limit procollagen's association with cell surface receptors like discoidin domain receptors (DDR), facilitating more efficient ECM integration.
SPARC and Transglutaminase Activity
Transglutaminases (TGs) are enzymes that catalyze the formation of covalent isopeptide bonds, and cross-linking ECM proteins like fibronectin and collagens. SPARC can serve as a TG2 substrate and has been shown to influence TG activity significantly. Enhanced TG activity on collagen I in SPARC-null tissues, such as the periodontal ligament (PDL), results in decreased mechanical strength and altered fibril morphology, which can be partially rescued by TG inhibitors.
Factor XIII, another transglutaminase, is implicated in bone biology by cross-linking plasma fibronectin (pFn) to support collagen network deposition, a critical step preceding bone mineralization. SPARC's role in moderating TG interactions with collagen remains a crucial area for future research.
SPARC-Null Bone Phenotype
SPARC-null mice exhibit significant differences in bone phenotype compared to wild-type (WT) mice, including early-onset osteopenia, decreased bone mineral density, and reduced biomechanical properties. These changes manifest more prominently in trabecular bone, which shows the greater reduction in volume and increased spacing over time.
The absence of SPARC correlates with lower osteoblast and osteoclast numbers, affecting bone formation rates. In addition, structural examination reveals increased mineral content and larger crystal sizes, alongside decreased turnover rates and compromised mechanical properties in cortical bone. Notably, alterations in crystal mineralization and apatite crystallite morphology in SPARC-null bones indicate SPARC's role in proper ECM assembly and mineralization.
Osteogenesis Imperfecta and SPARC Mutations
Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is primarily caused by mutations in the genes encoding collagen subunits (COL1A1 or COL1A2). Abnormal collagen synthesis in OI leads to diminished bone mass and increased fracture susceptibility. Recently, mutations in SPARC have also been identified in OI patients, introducing a new dimension to our understanding of this disorder.
Mutations in SPARC affecting its collagen-binding EC domain significantly reduce its collagen affinity, disrupting proper matrix assembly. Dermal fibroblasts from individuals with these mutations show delayed procollagen I secretion and altered fibril morphology, emphasizing SPARC's critical role in collagen deposition.
Regulation of Osteoblast and Osteoclast Activity by SPARC
SPARC influences both osteoblast and osteoclast activity, essential for bone remodeling. During osteoblast differentiation, SPARC protein levels increase during matrix deposition, despite relatively constant mRNA levels, indicating robust post-transcriptional regulation, notably by the miR-29 family.
SPARC-null mice display impaired osteoblast differentiation, with fewer osteoblastic precursors and heightened adipocyte differentiation. This shift suggests that SPARC is crucial for maintaining a balance between osteoblastogenesis and adipogenesis. SPARC-null mice also show reduced response to parathyroid hormone (PTH) treatment, an important anabolic therapy for osteoporosis, due to increased osteoclast activity and altered expression of osteoclastogenic markers.
Furthermore, SPARC's influence extends to monocyte/macrophage populations, which share lineage with osteoclast precursors. The absence of SPARC results in increased osteoclast formation, possibly mediated by direct cellular interactions or changes in the ECM environment.
Conclusion
SPARC plays a pivotal role in bone formation, maintenance, and pathology through its multiple functions in collagen processing, matrix assembly, and the regulation of osteoblast and osteoclast activity. The involvement of SPARC in fibrotic diseases and its critical association with collagen I expression underscores its importance in ECM production. The identification of SPARC mutations in OI patients highlights the necessity of further research to fully elucidate SPARC's mechanisms of action and potential therapeutic targets for bone pathology treatments. Understanding these processes not only enriches our knowledge of bone biology but also paves the way for novel interventions in bone-related disorders.
References
- Rosset E. M., Bradshaw A. D. SPARC/osteonectin in mineralized tissue. Matrix Biology. 2016, 52: 78-87.
- Kapinas K., et al. miR‐29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling. Journal of Cellular Biochemistry. 2009, 108(1): 216-224.
- Delany A. M., et al. Osteopenia and decreased bone formation in osteonectin-deficient mice. The Journal of Clinical Investigation. 2000, 105(7): 915-923.
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