Background: Bone remodeling depends on the dynamic balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Follistatin-like 1 (FSTL1) has been reported as an osteoclast-secreted protein that inhibits osteoclast differentiation, but its direct effects on osteoblast differentiation remain unclear. This study aimed to determine whether FSTL1 regulates osteoblast differentiation and mesenchymal stem cell migration and characterizes its role in osteoclast-osteoblast cellular cross-talk under in vitro conditions. Methods: Bone marrow-derived macrophages (BMMs) and stromal cells (BMSCs) from mice were used to induce osteoclast and osteoblast differentiation, respectively. Chemotaxis was assessed by Transwell migration, and osteoblast differentiation was evaluated in BMSC and MC3T3-E1 cells using staining, qRT-PCR, Western blotting, and proliferation assays. Results: FSTL1 significantly suppressed osteoclast differentiation and resorptive activity, confirmed by TRAP staining and pit assay, respectively. Expression of osteoclast markers such as NFATc1, TRAP, and DC-STAMP was reduced under FSTL1 treatment. In BMSCs, FSTL1 did not affect proliferation but significantly enhanced chemotaxis. Moreover, FSTL1 promoted osteogenic differentiation and mineralization, as demonstrated by increased ALP activity and Alizarin Red S staining. In MC3T3-E1 pre-osteoblasts, FSTL1 increased cell proliferation and mineralization by MTS and Alizarin Red staining. Key osteogenic markers, including Runx2 and osteocalcin, were also upregulated. Conclusions: Osteoclast-derived FSTL1 significantly suppresses osteoclastogenesis and promotes mesenchymal cell chemotaxis and osteogenic differentiation, indicating a role in regulating osteoclast–osteoblast cellular interactions in vitro. Targeting FSTL1 signaling may represent a promising therapeutic strategy for osteoporosis and other disorders of impaired bone remodeling.

Cartilage injury and osteoarthritis-associated degeneration remain major clinical challenges because articular cartilage is avascular, aneural, and alymphatic, leaving it with limited intrinsic capacity for repair. Current clinical strategies, including microfracture, osteochondral grafting, autologous chondrocyte implantation, and mesenchymal stem cell-based approaches, can relieve symptoms and partially restore tissue architecture. However, these approaches, particularly mesenchymal stem cell-based therapies, often produce fibrocartilage rather than durable hyaline cartilage and do not reliably reproduce the long-term mechanical competence or molecular identity of native articular cartilage. Induced pluripotent stem cells (iPSCs) have emerged as a promising alternative cell source for cartilage regeneration because they combine unlimited self-renewal with the capacity to generate patient-specific or allogeneic chondroprogenitors, articular chondrocytes, cartilage organoids, and engineered cartilage constructs. iPSC-derived chondrocytes also provide versatile platforms for modeling osteoarthritis and genetic skeletal disorders, performing genome editing, testing disease-modifying drugs, and developing personalized tissue-engineering systems. Nevertheless, clinical translation remains limited by protocol variability, incomplete lineage specification, hypertrophic differentiation, residual pluripotent cells, immune compatibility, tumorigenic risk, biomechanical immaturity, and the need for scalable Good Manufacturing Practice-compliant manufacturing. This review summarizes the developmental principles and molecular signaling networks that guide iPSC chondrogenesis, compares current differentiation and tissue-engineering strategies, and discusses therapeutic applications and key barriers that must be addressed to achieve safe, reproducible, and clinically effective iPSC-based cartilage repair.