Table 1 The role of main biochemistry substances in OA

Substance P (SP)

Neurokinin 1 receptor (NK1R)

Promote angiogenesis in the subchondral bone; contribute to cartilage degradation and synovial inflammation; mediate joint pain

^{158,159,160,161,162}

Prostaglandin E2 (PGE2)

Prostaglandin E (EP) 1–4 receptors

Disturb subchondral bone remodeling; promote innervation in the subchondral bone; regulate chondrocytes metabolism; mediate joint pain

^10,14,15,163

Nerve growth factor (NGF)

Tropomyosin receptor kinase A (TrkA)

Promote vascular and nerve growth in the subchondral bone; mediate hyperalgesia of OA synovium; mediate mechanical load-induced pain

^164,165,166

Transforming growth factor (TGF)-β

TGF-β receptor 1–3

Contribute to cartilage degeneration; lead to aberrant bone formation accompanied by increased angiogenesis

^61,167

Calcitonin-gene-related peptide (CGRP)

Calcitonin receptor-like receptor (CRLR)/ receptor activity modifying protein (RAMP) 1

Promote apoptosis and senescence of chondrocytes; inhibit the expression of chondrogenic markers

¹⁶⁸

α-melanocyte-stimulating hormone (α-MSH)

Melanocorticosteroid receptor 1 (MC1R)

Inhibit inflammation in the synovium and cartilage; play a chondroprotective role in cartilage

^169,170

Platelet-derived BB growth factor (PDGF-BB)

Platelet-derived growth factor receptor (PDGFR)-α; PDGFR-β

Induce abnormal angiogenesis and bone remodeling in OA subchondral bone

^14,171,172

Norepinephrine (NE) or noradrenaline (NA)

α1, α2, β1, β2, β3-adrenergic receptor (AR)

Protect cartilage from degeneration (β-AR); inhibit subchondral bone formation (β2-AR); induce the apoptosis of chondrocytes (α1-AR); inhibit the chondrogenic differentiation of synovial adipose stem cell (α2- AR)

^{96,173,174,175,176}

Vasoactive intestinal peptide (VIP)

Vasoactive intestinal peptide receptor (VIPR) 1, 2

Inhibit cartilage extracellular matrix (ECM) degradation; alleviates OA via inhibiting NF-κB signaling pathway

^177,178,179

Neuropeptide Y (NPY)

Y receptor 1 (Y1R); Y2R; Y4R; Y5R

Increases in OA synovial fluid and correlate to Watanabe pain scores; increases in dorsal root ganglion (DRG) of OA; exacerbate the OA progression

^180,181,182

Serotonin (5-HT)

5-HT 1-7 receptors

Repress cartilage regeneration; promote chondrocyte inflammation

^183,184