TABLE 2.

Potential beneficial treatment options for progressive KOA subtypes.

Progressive KOA subtypes		Treatment principle	Main altered molecules	Potential beneficial drugs
Cartilage degradation-driven subtype		Cartilage extra-cellular matrix components supplement	CTX-II, C2M, C2C, Coll 2-1, C-Col 10	Hyaluronic acid (Bannuru et al., 2011), Glucosamine (Fransen et al., 2015), Chondroitin (Fransen et al., 2015), Undenatured collagen II (Lugo et al., 2016)
Bone remodeling-driven subtype	Bone resorption	Anti-resorption	CTX-I, NTX-I, C1M, TRAP5b,	Bisphosphonate (Aitken et al., 2018), Osteoprotegerin (Sagar et al., 2014), Calcitonin (Karsdal et al., 2015), MIV-711 (Conaghan et al., 2019)
	Bone formation	N/A	ALP, PINP	N/A
Inflammation-driven subtype		Anti-inflammation	IL-1β, IL-1Ra, TNFα, IL-6, CCL3, CCL4	IL-1 inhibitor (Jotanovic et al., 2012), TNFα inhibitor (Grunke and Schulze-Koops, 2006), COX2 inhibitor (Hochberg et al., 2016), NSAIDs (Bannuru et al., 2019)
Pain-driven subtype		Analgesia, Anti-inflammation	hs-CRP, CRPM, bradykinin, CGRP, NGF	Opioids (Kolasinski et al., 2020), NSAIDs (Bannuru et al., 2019), NGF inhibitor (Berenbaum et al., 2020), CGRP inhibitor (Jin et al., 2018), Capsaicin (Kolasinski et al., 2020)

ALP, alkaline phosphatase; C1M, Collagen I degraded by matrix metalloproteinases; C2C, the cleavage neoepitope of collagen II; C2M, the fragments of collagen II degraded by matrix metalloproteinases; C-Col 10, C-terminus of collagen X; CCL3, CC-chemokine ligand 3; CCL4, CC-chemokine ligand 4; CGRP, calcitonin gene-related peptide; Coll 2-1 NO₂, nitrated form of Coll 2-1; COX2, cyclooxygenase 2; CRPM, the fragment of CRP; CTX-I, C-telopeptide of Col-I; CTX-II, C-telopeptide fragments of Col-II; hs-CRP, high sensitive CRP; IL-1β, interleukin 1β; IL-1Ra, IL-1 receptor antagonist; IL-6, interleukin 6; KOA, knee osteoarthritis; N/A, not available; NGF, nerve growth factor; NTX-I, N-telopeptide of Collagen I; NSAIDs, non-steroidal anti-inflammatory drugs; PINP, N-terminal collagen type I extension propeptide; TNFα, tumor necrosis factor α; TRAP5b, tartrate resistant acid phosphatase 5b.